Essential tremor, one of the most common movement disorders, affects about 4% of adults 40 years of age and older.¹ It is often referred to as familial tremor in patients with a family history of tremor. It has also been called benign tremor to differentiate it from tremor associated with neurodegenerative diseases, particularly Parkinson disease, but this condition is certainly not benign, as it can cause substantial functional impairment and difficulties with routine activities of daily living. The terms “essential” and “idiopathic” refer to the primary nature of the disorder and differentiate it from tremor that is a feature of a distinct neurologic entity or is secondary to a metabolic disease or drug therapy.

Successful management entails exclusion of secondary causes and careful selection of drug therapy. To date, there is no cure for essential tremor; all currently available treatments are purely symptomatic.

In this review, we outline the major diagnostic and therapeutic principles of managing essential tremor, indications for referral to specialists, and alternative and advanced therapeutic options.

CLINICAL PICTURE

Tremor is defined as rhythmic to-and-fro movement in any body part. It can be slow or fast, and its amplitude can be large and coarse, or small or even “fine.” It can appear at rest, with action, or during a sustained posture. In contrast to parkinsonian tremor (which presents mainly at rest), essential tremor is typically but not exclusively postural, kinetic, or both.

Postural tremor refers to tremor seen when the patient holds the affected limb (commonly the arm) unsupported against gravity. Kinetic tremor refers to tremor that appears with active movements. This is often demonstrated clinically by the finger-nose-finger test. Patients with essential tremor commonly have both postural and kinetic tremor.

The tremor commonly involves the arms, hands, and fingers.² Less commonly, it involves the head, the lips, the tongue, the legs, and the voice. In contrast to parkinsonian tremor, which typically affects one side of the body first, bilateral involvement is the general rule in essential tremor. However, one side of the body may be affected first, or may be more affected than the other. The frequency of the tremor ranges from 4 to 12 Hz (ie, beats per second).

The tremor usually starts in middle age and progresses slowly over time,³ but onset in old age or childhood is also possible.⁴ Both sexes are equally affected.

The tremor usually gets worse with anxiety, stress, and caffeine intake. It usually gets temporarily better with the consumption of small amounts of alcohol.

The functional impact of essential tremor is judged by its effect on different daily activities, especially writing, eating, drinking, dressing, manual work, and household chores.

In addition to motor dysfunction, the tremor can also have a significant psychological impact on the patient, because it usually gets worse in social situations.

Although it has long been thought that tremor is the sole neurologic sign of essential tremor, recent studies have shown that many patients have additional subtle findings, such as mild gait difficulty,⁵ slight incoordination,⁶ mild cognitive impairment,⁷ and decreased hearing,⁸ and are more likely to have anxiety and social phobia.⁹

Although different studies have varied in their findings, it is generally thought that about 50% of patients with essential tremor have a positive family history, often in a first-degree relative, suggesting autosomal dominant inheritance with variable penetrance.^10,11 Polygenetic and sporadic variants are also common.

DIFFERENTIAL DIAGNOSIS

Resting tremor

Resting tremor is typically an extrapyramidal sign and, when accompanied by rigidity and bradykinesia, is often part of a parkinsonian syndrome. It is most pronounced at rest when the affected body part is fully supported and stationary. The tremor tends to improve with action or posture. It usually has a “pill-rolling” character and, as mentioned, is associated with other extrapyramidal signs, such as rigidity, slowness, and, later on, postural instability.

About 20% of patients with essential tremor have resting tremor. These patients usually suffer from severe or long-standing disease.¹² However, the resting element in these cases is often milder than the postural and kinetic components, and it is typically not associated with other extrapyramidal signs. Also, some patients may have both essential tremor and Parkinson disease.¹³

Intentional tremor

Pure intentional tremor is usually seen with cerebellar pathology, which includes tumors, stroke, multiple sclerosis, trauma, and spinocerebellar degeneration. The amplitude of this type of tremor increases as the affected limb approaches the final target. It can best be demonstrated clinically by the finger-nose-finger test. The frequency of intentional tremor is slow (2 to 4 Hz) and is usually associated with other cerebellar signs, such as dysmetria, decomposition, rebound, and dysdiadochokinesia (ie, the inability to perform rapid alternating movements in a smooth and coordinated manner).

About 50% of patients with essential tremor have an intentional component to their tremor,⁶ or it can be mildly present in the form of a slight gait difficulty. However, in essential tremor, other features of cerebellar dysfunction are either absent or only very slight.

 

 

Secondary causes of postural-kinetic tremor

Enhanced physiologic tremor. A very mild postural tremor is present in almost all people and is considered “physiologic” since it has almost no clinical significance. This type of tremor is often invisible, but when “enhanced,” it can be visually demonstrated by placing a piece of paper over the stretched hands and watching the ripple from the paper.

Certain conditions can aggravate this physiologic tremor and can make it symptomatic. Common causes include anxiety, sleep deprivation, hypoglycemia, hyperthyroidism, pheochromocytoma, serotonin syndrome, and carcinoid syndrome.

Metabolic tremor. Hyperammonemia can cause tremor in patients with hepatic encephalopathy, and uremia can cause tremor in patients with renal failure. These metabolic conditions classically result in “flappy” tremor (asterixis), a special form of postural tremor characterized by jerking movements with high amplitude. It is best seen when the patient stretches out the arms and extends the wrists as if trying to stop traffic. But even though it may look like tremor, asterixis is thought to be a form of “negative” myoclonus.

Drug-related tremor. Postural-kinetic tremor can be induced by drugs, including lithium (Lithobid), valproate (Depakote), amiodarone (Cordarone), central nervous system stimulants, beta agonists (including inhalers), and some antidepressants. Tremor can also occur with alcohol or sedative withdrawal.

Psychogenic tremor. Tremor can be seen as part of a somatoform disorder commonly referred to as conversion disorder or conversion reaction. Psychogenic tremor is characterized by acute onset, commonly following a psychosocial stressor; it is often atypical, variable in frequency, amplitude, and body-part involvement, and it can readily be interrupted on examination by distracting the patient.

Neurologic disorders. The postural and kinetic elements of essential tremor may also be seen in the following neurologic conditions:

• Holmes (rubral) tremor, a combination of resting, postural, kinetic, and intentional tremor of low frequency and high amplitude. It usually has a proximal component and is often unilateral. It commonly is due to a lesion that involves the brainstem, eg, red nucleus, inferior olive, cerebellum, or thalamus. Common causes include stroke, prolonged hypoxia, and head trauma (including closed-head trauma with negative imaging). This type of tremor is usually associated with ataxia.¹⁴
• Dystonic tremor is predominantly postural and is associated with abnormal dystonic posturing of the affected body part, commonly the head, hands, or feet. Unlike the rhythmic oscillations of essential tremor, dystonic tremor is often irregular in rhythm.
• Multiple sclerosis can present with a combination of postural, kinetic, and intentional tremor. Patients usually have a clear history of recurrent neurologic deficits and show a combination of pyramidal, cerebellar, and sensory signs on examination consistent with multiple sclerosis.¹⁵
• Neuropathic tremor is seen in a small proportion of patients with peripheral neuropathy, especially demyelinating neuropathy.¹⁶ The tremor is usually posturalkinetic and is associated with signs of neuropathy, such as a glove-and-stocking pattern of hypoesthesia, reduced reflexes, and sensory ataxia (including intentional tremor when the eyes are closed).
• Posttraumatic tremor can occur after severe or even mild head trauma, especially in children. It is commonly rubral, but other types have been reported, including a presentation resembling essential tremor.¹⁷
• Monosymptomatic or isolated tremor. A number of conditions related to essential tremor with location-specific or task-specific tremor have been described. These rare conditions historically have been classified as “possible essential tremor” or “essential tremor variants” but are now considered separate entities. These include task-specific tremor (eg, writing tremor), isolated head tremor, isolated voice tremor, and orthostatic tremor (tremor in the legs and trunk upon standing in place, but not when sitting or walking).^18,19

DIAGNOSIS IS CLINICAL

Essential tremor is a clinical diagnosis. After a thorough review of the medical history and medication exposures, laboratory and imaging tests may be ordered to rule out a secondary cause. A complete metabolic panel, including blood glucose and thyroid-stimulating hormone levels, is usually sufficient. Brain imaging or other imaging is ordered for patients with an atypical presentation.

TREATMENT IS SYMPTOMATIC

Treatment of essential tremor is symptomatic. Several drugs of different pharmacologic classes can reduce the severity of the tremor and improve function.

Choosing the appropriate treatment depends on the type of tremor and the presence of associated conditions. The response to treatment and the development of side effects guide further adjustments. The following is a brief description of the available antitremor agents.

FIRST-LINE AGENTS

Propranolol

Propranolol (Inderal), a nonselective beta blocker, is the most widely used antitremor drug and the only agent approved by the US Food and Drug Administration for essential tremor. It should be started at a low dose and titrated upward gradually. The usual starting dose is 10 mg three times daily. The average effective dose is 120 mg daily. The dose can be increased up to 320 mg if needed and tolerated.

Sustained-release preparations are equally effective and are given as a single daily dose to improve compliance.²⁰

Propranolol improves tremor in 50% to 70% of patients with essential tremor and achieves an average tremor reduction of 50% to 60%.^1,21–25 Side effects include bronchoconstriction, bradycardia, hypotension, depression, impotence, fatigue, and gastrointestinal disturbances.

Other beta-blockers, such as nadolol (Corgard) and timolol, are also effective against tremor but are less potent than propranolol.^26,27 The selective beta-1-blocker metoprolol (Lopressor) may be effective and has fewer noncardiac side effects than propranolol.²⁸ It can be used in patients who discontinue propranolol because of adverse effects. Atenolol (Tenormin) and pindolol (Visken) have little or no effect on tremor.²⁹

A good candidate for propranolol therapy in essential tremor is:

• A patient with no known contraindication to propranolol
• A patient with hypertension, coronary heart disease, or tachyarrhythmia
• A patient with anxiety or social phobia.

Absolute contraindications to propranolol are:

• Moderate to severe bronchial asthma
• Significant bradycardia or heart block
• Symptomatic hypotension
• End-stage heart failure
• Concurrent use of a calcium channel blocker.

Relative contraindications are:

• Wheezing (eg, chronic obstructive pulmonary disease)
• Depression
• Diabetes mellitus in a patient more prone to hypoglycemia (propranolol masks the warning signs of hypoglycemia)
• Reduced sexual potency in a male patient.

 

 

Primidone

Primidone (Mysoline) is an antiepileptic drug structurally similar to barbiturates. Its antitremor effect is equal to that of propranolol, though some studies suggest it is slightly more efficacious.^30,31

It should be started at a low dose, ie, 25 mg once daily at bedtime. The dose should then be increased gradually until satisfactory and tolerable tremor control is achieved. Most patients respond to doses of around 250 mg per day.^1,22,24–25 The dose can be increased if needed and tolerated.

Primidone reduces tremor by about 50% to 60%.^1,22,24–25 Side effects include sedation, dizziness, fatigue, nausea, and depression, as well as ataxia and confusion in severe cases.

A good candidate for primidone in essential tremor is:

• A patient with no known contraindication to primidone
• A patient with contraindications to propranolol
• A younger patient
• A patient with epilepsy.

Absolute contraindications to primidone include:

• Confusion or dementia
• Oral anticoagulant therapy with difficulty controlling the International Normalized Ratio (primidone is a potent enzyme inducer).

Relative contraindications to primidone in essential tremor are:

• Depression
• Alcohol abuse
• Ongoing therapy with sedating drugs
• Ataxia or vertigo.

SECOND-LINE AGENTS

Other antiepileptics

Topiramate (Topamax) is a broad-spectrum antiepileptic shown to be significantly effective against essential tremor.³² It is usually started at a single daily dose of 25 mg and increased gradually to the most effective dose, usually around 300 mg.

Side effects include reduced appetite, weight loss, cognitive dysfunction, and paresthesia.

Favorable candidates include patients who are epileptic or overweight. Contraindications include cognitive impairment and low body weight. It is also not recommended in children so as to avoid any possible negative effect on cognitive development. In rare cases, topiramate has been reported to cause significant visual disturbances.

Gabapentin (Neurontin) is an antiepileptic that is now more often used as a symptomatic treatment for neuropathic pain. Studies have suggested a beneficial effect on essential tremor,^33,34 but some investigators have questioned its efficacy.³⁵

Like other antitremor agents, it should be started at a low dose, ie, around 300 mg, and escalated gradually until the tremor is controlled. The usual effective dose is 1,200 mg.

Gabapentin is generally well tolerated, and side effects such as dizziness, drowsiness, sedation, and unsteadiness are rare and usually mild.

The favorable candidate is a patient with associated neuropathy or multiple comorbidities. Gabapentin has also been reported to alleviate neuropathic tremor.

Contraindications are minimal and include intolerability or hypersensitivity to the drug. It also should be avoided in patients at a high risk of falling.

Levetiracetam (Keppra) is a novel antiepileptic effective against partial seizures. Studies have shown contradictory results regarding its antitremor effect. One double-blind, placebo-controlled study demonstrated significant reduction in essential tremor with 1,000 mg of levetiracetam.³⁶ However, its effect on tremor is believed to be short-lived, and some studies argue against its efficacy.³⁷ It has a favorable side-effect profile and is generally very well tolerated. It can be used as an adjunct to other antitremor agents and is preferred for patients with coexisting partial seizures or myoclonus.

Benzodiazepines. Minor tranquilizers are often used to control tremor, especially in coexisting anxiety or insomnia. Alprazolam (Xanax) is the one most widely used for this indication.³⁸ It can be started in a dose of 0.25 mg once at bedtime and increased gradually up to 0.75 to 2 mg. Clonazepam (Klonopin) is particularly useful for orthostatic tremor, a variant of essential tremor characterized by tremor of the legs and trunk upon standing.³⁹

Common side effects of benzodiazepines include sedation, cognitive dysfunction, hypotension, respiratory inhibition, and addiction after prolonged use. In the elderly, they can lead to confusion and disinhibition and can increase the risk of falling. They should be avoided in the elderly and in alcoholic patients and those with a high risk of substance abuse.

Stopping benzodiazepines should be done gradually to avoid withdrawal symptoms, including aggravation of tremor.

THIRD-LINE AGENTS

Clozapine

Clozapine (Clozaril) is a novel antipsychotic drug with no extrapyramidal side effects. It has been reported effective in essential tremor and drug-induced tremor,^40,41 but the results of these early studies have not been confirmed.

Clozapine is started as a single daily dose of 12.5 mg and is increased up to 75 mg or 100 mg. It is an attractive option for patients with coexisting psychosis, bipolar disorder, or chorea. Its main side effects are sedation, salivation, weight gain, hypertension, diabetes, and seizures.

One especially serious side effect is agranulocytosis. This potentially fatal effect is rare, occurring in about 1.3% of patients receiving this drug. Weekly monitoring of the white blood cell count is mandated during treatment with clozapine, and this has made clozapine a less attractive option for the routine treatment of essential tremor.

Mirtazapine

Mirtazapine (Remeron) is a novel antidepressant widely used in Parkinson disease as both an antidepressant and a sleeping aid. Case studies have reported efficacy in both essential tremor and parkinsonian tremor,⁴² but controlled studies have not confirmed this.⁴³ Mirtazapine is a reasonable option in patients with coexisting depression or insomnia. It is usually given as a single bedtime dose of 15 to 30 mg.

Other drugs

Studies of other agents for the treatment of essential tremor—eg, carbonic anhydrase enzyme inhibitors, calcium channel blockers, isoniazid (Tubizid), clonidine (Catapres), phenobarbital, and theophylline—have yielded highly contradictory results. Thus, they are not recommended as first- or second-line agents for essential tremor.

SPECIALTY-LEVEL CARE

When essential tremor does not respond to drug therapy or the patient cannot tolerate drug therapy, the patient should be referred to a center specializing in movement disorders for more advanced treatment options, ie, botulinum toxin injection and deep brain stimulation surgery.

Botulinum toxin

Botulinum toxin type A has been studied for the treatment of essential tremor with variable degrees of success. It has been effective in reducing hand tremor in essential tremor, but without a concomitant improvement in functional disability.⁴⁴ This limited functional improvement has been attributed to the development of muscle weakness after injection of the neurotoxin. This has also raised questions about unintentional unblinding when interpreting study results. Therefore, most clinicians restrict its use to focal forms of tremor such as voice tremor,⁴⁵ head tremor, and task-specific tremor.

Side effects are limited and temporary and include muscle weakness, pain at the injection site, dysphagia (when injected for head or voice tremor), and a breathy vocal quality (when injected for voice tremor). Botulinum toxin injection is the treatment of choice for focal dystonia, and therefore would be a good option for dystonic tremor.

Thalamic deep brain stimulation

This technique involves stereotactic implantation of a stimulation lead in the ventral intermediate nucleus of the thalamus. The lead connects via a subcutaneous wire to an intermittent pulse generator, implanted subcutaneously in the infraclavicular region. The stimulation lead produces continuous stimulation of the ventralis intermedius nucleus that is functionally equal to lesional surgery, thus antagonizing the relay of tremor signals at the thalamus.

The battery of the pulse generator must be replaced every 4 to 7 years depending on usage and stimulation parameters. Battery replacement can be performed with minor surgery at the infraclavicular region.

Thalamic deep brain stimulation is indicated for patients with severe, disabling essential tremor who have tremor resistant to drug therapy or who cannot tolerate drug therapy.

The procedure has been shown to provide benefit in 90% of patients, with more than an 80% improvement in tremor severity and functional impact.^46–49 Deep brain stimulation is effective against tremor affecting parts of the body other than the limbs, including the head; an exception to this is voice tremor, which usually does not improve dramatically. The procedure can be done unilaterally or bilaterally, depending on symptoms. Patients with asymmetrical tremor and those at risk of side effects can undergo unilateral surgery. Bilateral treatment is recommended for patients with symmetric tremor or significant head tremor, or who are young and healthy.

Surgical risks include brain hemorrhage and infection. Side effects of the stimulation include paresthesias, paresis, imbalance, dysarthria, and, in rare cases, dysphagia.

CHOOSING THE BEST MANAGEMENT PLAN FOR YOUR PATIENT

The choice of treatment may be challenging, given the multiple treatment options and the variability of tremor severity from one patient to another. The following guidelines can be used to help make this decision.

All patients should be advised to reduce caffeine intake, to have sufficient hours of sleep, and to avoid stressful situations.

Patients with minor, nondisabling tremor can be left untreated if the tremors are not bothersome or if the patient prefers not to pursue active treatment.

In patients who have bothersome tremor only when anxious or in certain social situations, give propranolol or alprazolam (or both) to be taken as needed. Relaxation techniques and meditation are also useful for these patients.

Patients with constant bothersome tremor should be started on either propranolol or primidone based on the patient’s profile and propensity to develop side effects from each of these drugs. The dosing should be optimized gradually according to the patient’s response and the drug’s tolerability.

If essential tremor is not sufficiently controlled with one first-line agent (propranolol or primidone), try combining the two first-line agents if the patient finds it tolerable.

A second-line agent can be added to either of the first-line agents or to the combination of both if tremor control is not yet sufficient. A second-line or third-line agent can also be used as the primary treatment if both first-line agents are contraindicated or intolerable. Combining two or more second- and third-line agents is another option. The choice of second- or third-line agent should be guided by the patient’s characteristics and comorbidities in relation to the agent’s side effects and contraindications as detailed in the above section.

Patients should be referred to a movement disorders specialist in cases of resistant tremor, intolerance to oral medications, severe disability, and atypical presentation. Types of tremor known to be poorly responsive to oral medications (eg, head tremor, voice tremor) deserve a specialist evaluation if they contribute significantly to the patient’s morbidity.

The usual specialist treatment of severe voice tremor and head tremor is botulinum toxin injection. Patients with resistant and disabling hand tremor are evaluated for thalamic deep brain stimulation.

Patients with residual disability despite medical and surgical treatment should be referred for occupational therapy. Occupational therapy can improve quality of life through the use of special utensils, pens, computer gadgets, and arm weights, among other devices.

Essential tremor, one of the most common movement disorders, affects about 4% of adults 40 years of age and older.¹ It is often referred to as familial tremor in patients with a family history of tremor. It has also been called benign tremor to differentiate it from tremor associated with neurodegenerative diseases, particularly Parkinson disease, but this condition is certainly not benign, as it can cause substantial functional impairment and difficulties with routine activities of daily living. The terms “essential” and “idiopathic” refer to the primary nature of the disorder and differentiate it from tremor that is a feature of a distinct neurologic entity or is secondary to a metabolic disease or drug therapy.

Successful management entails exclusion of secondary causes and careful selection of drug therapy. To date, there is no cure for essential tremor; all currently available treatments are purely symptomatic.

In this review, we outline the major diagnostic and therapeutic principles of managing essential tremor, indications for referral to specialists, and alternative and advanced therapeutic options.

CLINICAL PICTURE

Tremor is defined as rhythmic to-and-fro movement in any body part. It can be slow or fast, and its amplitude can be large and coarse, or small or even “fine.” It can appear at rest, with action, or during a sustained posture. In contrast to parkinsonian tremor (which presents mainly at rest), essential tremor is typically but not exclusively postural, kinetic, or both.

Postural tremor refers to tremor seen when the patient holds the affected limb (commonly the arm) unsupported against gravity. Kinetic tremor refers to tremor that appears with active movements. This is often demonstrated clinically by the finger-nose-finger test. Patients with essential tremor commonly have both postural and kinetic tremor.

The tremor commonly involves the arms, hands, and fingers.² Less commonly, it involves the head, the lips, the tongue, the legs, and the voice. In contrast to parkinsonian tremor, which typically affects one side of the body first, bilateral involvement is the general rule in essential tremor. However, one side of the body may be affected first, or may be more affected than the other. The frequency of the tremor ranges from 4 to 12 Hz (ie, beats per second).

The tremor usually starts in middle age and progresses slowly over time,³ but onset in old age or childhood is also possible.⁴ Both sexes are equally affected.

The tremor usually gets worse with anxiety, stress, and caffeine intake. It usually gets temporarily better with the consumption of small amounts of alcohol.

The functional impact of essential tremor is judged by its effect on different daily activities, especially writing, eating, drinking, dressing, manual work, and household chores.

In addition to motor dysfunction, the tremor can also have a significant psychological impact on the patient, because it usually gets worse in social situations.

Although it has long been thought that tremor is the sole neurologic sign of essential tremor, recent studies have shown that many patients have additional subtle findings, such as mild gait difficulty,⁵ slight incoordination,⁶ mild cognitive impairment,⁷ and decreased hearing,⁸ and are more likely to have anxiety and social phobia.⁹

Although different studies have varied in their findings, it is generally thought that about 50% of patients with essential tremor have a positive family history, often in a first-degree relative, suggesting autosomal dominant inheritance with variable penetrance.^10,11 Polygenetic and sporadic variants are also common.

DIFFERENTIAL DIAGNOSIS

Resting tremor

Resting tremor is typically an extrapyramidal sign and, when accompanied by rigidity and bradykinesia, is often part of a parkinsonian syndrome. It is most pronounced at rest when the affected body part is fully supported and stationary. The tremor tends to improve with action or posture. It usually has a “pill-rolling” character and, as mentioned, is associated with other extrapyramidal signs, such as rigidity, slowness, and, later on, postural instability.

About 20% of patients with essential tremor have resting tremor. These patients usually suffer from severe or long-standing disease.¹² However, the resting element in these cases is often milder than the postural and kinetic components, and it is typically not associated with other extrapyramidal signs. Also, some patients may have both essential tremor and Parkinson disease.¹³

Intentional tremor

Pure intentional tremor is usually seen with cerebellar pathology, which includes tumors, stroke, multiple sclerosis, trauma, and spinocerebellar degeneration. The amplitude of this type of tremor increases as the affected limb approaches the final target. It can best be demonstrated clinically by the finger-nose-finger test. The frequency of intentional tremor is slow (2 to 4 Hz) and is usually associated with other cerebellar signs, such as dysmetria, decomposition, rebound, and dysdiadochokinesia (ie, the inability to perform rapid alternating movements in a smooth and coordinated manner).

About 50% of patients with essential tremor have an intentional component to their tremor,⁶ or it can be mildly present in the form of a slight gait difficulty. However, in essential tremor, other features of cerebellar dysfunction are either absent or only very slight.

 

 

Secondary causes of postural-kinetic tremor

Enhanced physiologic tremor. A very mild postural tremor is present in almost all people and is considered “physiologic” since it has almost no clinical significance. This type of tremor is often invisible, but when “enhanced,” it can be visually demonstrated by placing a piece of paper over the stretched hands and watching the ripple from the paper.

Certain conditions can aggravate this physiologic tremor and can make it symptomatic. Common causes include anxiety, sleep deprivation, hypoglycemia, hyperthyroidism, pheochromocytoma, serotonin syndrome, and carcinoid syndrome.

Metabolic tremor. Hyperammonemia can cause tremor in patients with hepatic encephalopathy, and uremia can cause tremor in patients with renal failure. These metabolic conditions classically result in “flappy” tremor (asterixis), a special form of postural tremor characterized by jerking movements with high amplitude. It is best seen when the patient stretches out the arms and extends the wrists as if trying to stop traffic. But even though it may look like tremor, asterixis is thought to be a form of “negative” myoclonus.

Drug-related tremor. Postural-kinetic tremor can be induced by drugs, including lithium (Lithobid), valproate (Depakote), amiodarone (Cordarone), central nervous system stimulants, beta agonists (including inhalers), and some antidepressants. Tremor can also occur with alcohol or sedative withdrawal.

Psychogenic tremor. Tremor can be seen as part of a somatoform disorder commonly referred to as conversion disorder or conversion reaction. Psychogenic tremor is characterized by acute onset, commonly following a psychosocial stressor; it is often atypical, variable in frequency, amplitude, and body-part involvement, and it can readily be interrupted on examination by distracting the patient.

Neurologic disorders. The postural and kinetic elements of essential tremor may also be seen in the following neurologic conditions:

• Holmes (rubral) tremor, a combination of resting, postural, kinetic, and intentional tremor of low frequency and high amplitude. It usually has a proximal component and is often unilateral. It commonly is due to a lesion that involves the brainstem, eg, red nucleus, inferior olive, cerebellum, or thalamus. Common causes include stroke, prolonged hypoxia, and head trauma (including closed-head trauma with negative imaging). This type of tremor is usually associated with ataxia.¹⁴
• Dystonic tremor is predominantly postural and is associated with abnormal dystonic posturing of the affected body part, commonly the head, hands, or feet. Unlike the rhythmic oscillations of essential tremor, dystonic tremor is often irregular in rhythm.
• Multiple sclerosis can present with a combination of postural, kinetic, and intentional tremor. Patients usually have a clear history of recurrent neurologic deficits and show a combination of pyramidal, cerebellar, and sensory signs on examination consistent with multiple sclerosis.¹⁵
• Neuropathic tremor is seen in a small proportion of patients with peripheral neuropathy, especially demyelinating neuropathy.¹⁶ The tremor is usually posturalkinetic and is associated with signs of neuropathy, such as a glove-and-stocking pattern of hypoesthesia, reduced reflexes, and sensory ataxia (including intentional tremor when the eyes are closed).
• Posttraumatic tremor can occur after severe or even mild head trauma, especially in children. It is commonly rubral, but other types have been reported, including a presentation resembling essential tremor.¹⁷
• Monosymptomatic or isolated tremor. A number of conditions related to essential tremor with location-specific or task-specific tremor have been described. These rare conditions historically have been classified as “possible essential tremor” or “essential tremor variants” but are now considered separate entities. These include task-specific tremor (eg, writing tremor), isolated head tremor, isolated voice tremor, and orthostatic tremor (tremor in the legs and trunk upon standing in place, but not when sitting or walking).^18,19

DIAGNOSIS IS CLINICAL

Essential tremor is a clinical diagnosis. After a thorough review of the medical history and medication exposures, laboratory and imaging tests may be ordered to rule out a secondary cause. A complete metabolic panel, including blood glucose and thyroid-stimulating hormone levels, is usually sufficient. Brain imaging or other imaging is ordered for patients with an atypical presentation.

TREATMENT IS SYMPTOMATIC

Treatment of essential tremor is symptomatic. Several drugs of different pharmacologic classes can reduce the severity of the tremor and improve function.

Choosing the appropriate treatment depends on the type of tremor and the presence of associated conditions. The response to treatment and the development of side effects guide further adjustments. The following is a brief description of the available antitremor agents.

FIRST-LINE AGENTS

Propranolol

Propranolol (Inderal), a nonselective beta blocker, is the most widely used antitremor drug and the only agent approved by the US Food and Drug Administration for essential tremor. It should be started at a low dose and titrated upward gradually. The usual starting dose is 10 mg three times daily. The average effective dose is 120 mg daily. The dose can be increased up to 320 mg if needed and tolerated.

Sustained-release preparations are equally effective and are given as a single daily dose to improve compliance.²⁰

Propranolol improves tremor in 50% to 70% of patients with essential tremor and achieves an average tremor reduction of 50% to 60%.^1,21–25 Side effects include bronchoconstriction, bradycardia, hypotension, depression, impotence, fatigue, and gastrointestinal disturbances.

Other beta-blockers, such as nadolol (Corgard) and timolol, are also effective against tremor but are less potent than propranolol.^26,27 The selective beta-1-blocker metoprolol (Lopressor) may be effective and has fewer noncardiac side effects than propranolol.²⁸ It can be used in patients who discontinue propranolol because of adverse effects. Atenolol (Tenormin) and pindolol (Visken) have little or no effect on tremor.²⁹

A good candidate for propranolol therapy in essential tremor is:

• A patient with no known contraindication to propranolol
• A patient with hypertension, coronary heart disease, or tachyarrhythmia
• A patient with anxiety or social phobia.

Absolute contraindications to propranolol are:

• Moderate to severe bronchial asthma
• Significant bradycardia or heart block
• Symptomatic hypotension
• End-stage heart failure
• Concurrent use of a calcium channel blocker.

Relative contraindications are:

• Wheezing (eg, chronic obstructive pulmonary disease)
• Depression
• Diabetes mellitus in a patient more prone to hypoglycemia (propranolol masks the warning signs of hypoglycemia)
• Reduced sexual potency in a male patient.

 

 

Primidone

Primidone (Mysoline) is an antiepileptic drug structurally similar to barbiturates. Its antitremor effect is equal to that of propranolol, though some studies suggest it is slightly more efficacious.^30,31

It should be started at a low dose, ie, 25 mg once daily at bedtime. The dose should then be increased gradually until satisfactory and tolerable tremor control is achieved. Most patients respond to doses of around 250 mg per day.^1,22,24–25 The dose can be increased if needed and tolerated.

Primidone reduces tremor by about 50% to 60%.^1,22,24–25 Side effects include sedation, dizziness, fatigue, nausea, and depression, as well as ataxia and confusion in severe cases.

A good candidate for primidone in essential tremor is:

• A patient with no known contraindication to primidone
• A patient with contraindications to propranolol
• A younger patient
• A patient with epilepsy.

Absolute contraindications to primidone include:

• Confusion or dementia
• Oral anticoagulant therapy with difficulty controlling the International Normalized Ratio (primidone is a potent enzyme inducer).

Relative contraindications to primidone in essential tremor are:

• Depression
• Alcohol abuse
• Ongoing therapy with sedating drugs
• Ataxia or vertigo.

SECOND-LINE AGENTS

Other antiepileptics

Topiramate (Topamax) is a broad-spectrum antiepileptic shown to be significantly effective against essential tremor.³² It is usually started at a single daily dose of 25 mg and increased gradually to the most effective dose, usually around 300 mg.

Side effects include reduced appetite, weight loss, cognitive dysfunction, and paresthesia.

Favorable candidates include patients who are epileptic or overweight. Contraindications include cognitive impairment and low body weight. It is also not recommended in children so as to avoid any possible negative effect on cognitive development. In rare cases, topiramate has been reported to cause significant visual disturbances.

Gabapentin (Neurontin) is an antiepileptic that is now more often used as a symptomatic treatment for neuropathic pain. Studies have suggested a beneficial effect on essential tremor,^33,34 but some investigators have questioned its efficacy.³⁵

Like other antitremor agents, it should be started at a low dose, ie, around 300 mg, and escalated gradually until the tremor is controlled. The usual effective dose is 1,200 mg.

Gabapentin is generally well tolerated, and side effects such as dizziness, drowsiness, sedation, and unsteadiness are rare and usually mild.

The favorable candidate is a patient with associated neuropathy or multiple comorbidities. Gabapentin has also been reported to alleviate neuropathic tremor.

Contraindications are minimal and include intolerability or hypersensitivity to the drug. It also should be avoided in patients at a high risk of falling.

Levetiracetam (Keppra) is a novel antiepileptic effective against partial seizures. Studies have shown contradictory results regarding its antitremor effect. One double-blind, placebo-controlled study demonstrated significant reduction in essential tremor with 1,000 mg of levetiracetam.³⁶ However, its effect on tremor is believed to be short-lived, and some studies argue against its efficacy.³⁷ It has a favorable side-effect profile and is generally very well tolerated. It can be used as an adjunct to other antitremor agents and is preferred for patients with coexisting partial seizures or myoclonus.

Benzodiazepines. Minor tranquilizers are often used to control tremor, especially in coexisting anxiety or insomnia. Alprazolam (Xanax) is the one most widely used for this indication.³⁸ It can be started in a dose of 0.25 mg once at bedtime and increased gradually up to 0.75 to 2 mg. Clonazepam (Klonopin) is particularly useful for orthostatic tremor, a variant of essential tremor characterized by tremor of the legs and trunk upon standing.³⁹

Common side effects of benzodiazepines include sedation, cognitive dysfunction, hypotension, respiratory inhibition, and addiction after prolonged use. In the elderly, they can lead to confusion and disinhibition and can increase the risk of falling. They should be avoided in the elderly and in alcoholic patients and those with a high risk of substance abuse.

Stopping benzodiazepines should be done gradually to avoid withdrawal symptoms, including aggravation of tremor.

THIRD-LINE AGENTS

Clozapine

Clozapine (Clozaril) is a novel antipsychotic drug with no extrapyramidal side effects. It has been reported effective in essential tremor and drug-induced tremor,^40,41 but the results of these early studies have not been confirmed.

Clozapine is started as a single daily dose of 12.5 mg and is increased up to 75 mg or 100 mg. It is an attractive option for patients with coexisting psychosis, bipolar disorder, or chorea. Its main side effects are sedation, salivation, weight gain, hypertension, diabetes, and seizures.

One especially serious side effect is agranulocytosis. This potentially fatal effect is rare, occurring in about 1.3% of patients receiving this drug. Weekly monitoring of the white blood cell count is mandated during treatment with clozapine, and this has made clozapine a less attractive option for the routine treatment of essential tremor.

Mirtazapine

Mirtazapine (Remeron) is a novel antidepressant widely used in Parkinson disease as both an antidepressant and a sleeping aid. Case studies have reported efficacy in both essential tremor and parkinsonian tremor,⁴² but controlled studies have not confirmed this.⁴³ Mirtazapine is a reasonable option in patients with coexisting depression or insomnia. It is usually given as a single bedtime dose of 15 to 30 mg.

Other drugs

Studies of other agents for the treatment of essential tremor—eg, carbonic anhydrase enzyme inhibitors, calcium channel blockers, isoniazid (Tubizid), clonidine (Catapres), phenobarbital, and theophylline—have yielded highly contradictory results. Thus, they are not recommended as first- or second-line agents for essential tremor.

SPECIALTY-LEVEL CARE

When essential tremor does not respond to drug therapy or the patient cannot tolerate drug therapy, the patient should be referred to a center specializing in movement disorders for more advanced treatment options, ie, botulinum toxin injection and deep brain stimulation surgery.

Botulinum toxin

Botulinum toxin type A has been studied for the treatment of essential tremor with variable degrees of success. It has been effective in reducing hand tremor in essential tremor, but without a concomitant improvement in functional disability.⁴⁴ This limited functional improvement has been attributed to the development of muscle weakness after injection of the neurotoxin. This has also raised questions about unintentional unblinding when interpreting study results. Therefore, most clinicians restrict its use to focal forms of tremor such as voice tremor,⁴⁵ head tremor, and task-specific tremor.

Side effects are limited and temporary and include muscle weakness, pain at the injection site, dysphagia (when injected for head or voice tremor), and a breathy vocal quality (when injected for voice tremor). Botulinum toxin injection is the treatment of choice for focal dystonia, and therefore would be a good option for dystonic tremor.

Thalamic deep brain stimulation

This technique involves stereotactic implantation of a stimulation lead in the ventral intermediate nucleus of the thalamus. The lead connects via a subcutaneous wire to an intermittent pulse generator, implanted subcutaneously in the infraclavicular region. The stimulation lead produces continuous stimulation of the ventralis intermedius nucleus that is functionally equal to lesional surgery, thus antagonizing the relay of tremor signals at the thalamus.

The battery of the pulse generator must be replaced every 4 to 7 years depending on usage and stimulation parameters. Battery replacement can be performed with minor surgery at the infraclavicular region.

Thalamic deep brain stimulation is indicated for patients with severe, disabling essential tremor who have tremor resistant to drug therapy or who cannot tolerate drug therapy.

The procedure has been shown to provide benefit in 90% of patients, with more than an 80% improvement in tremor severity and functional impact.^46–49 Deep brain stimulation is effective against tremor affecting parts of the body other than the limbs, including the head; an exception to this is voice tremor, which usually does not improve dramatically. The procedure can be done unilaterally or bilaterally, depending on symptoms. Patients with asymmetrical tremor and those at risk of side effects can undergo unilateral surgery. Bilateral treatment is recommended for patients with symmetric tremor or significant head tremor, or who are young and healthy.

Surgical risks include brain hemorrhage and infection. Side effects of the stimulation include paresthesias, paresis, imbalance, dysarthria, and, in rare cases, dysphagia.

CHOOSING THE BEST MANAGEMENT PLAN FOR YOUR PATIENT

The choice of treatment may be challenging, given the multiple treatment options and the variability of tremor severity from one patient to another. The following guidelines can be used to help make this decision.

All patients should be advised to reduce caffeine intake, to have sufficient hours of sleep, and to avoid stressful situations.

Patients with minor, nondisabling tremor can be left untreated if the tremors are not bothersome or if the patient prefers not to pursue active treatment.

In patients who have bothersome tremor only when anxious or in certain social situations, give propranolol or alprazolam (or both) to be taken as needed. Relaxation techniques and meditation are also useful for these patients.

Patients with constant bothersome tremor should be started on either propranolol or primidone based on the patient’s profile and propensity to develop side effects from each of these drugs. The dosing should be optimized gradually according to the patient’s response and the drug’s tolerability.

If essential tremor is not sufficiently controlled with one first-line agent (propranolol or primidone), try combining the two first-line agents if the patient finds it tolerable.

A second-line agent can be added to either of the first-line agents or to the combination of both if tremor control is not yet sufficient. A second-line or third-line agent can also be used as the primary treatment if both first-line agents are contraindicated or intolerable. Combining two or more second- and third-line agents is another option. The choice of second- or third-line agent should be guided by the patient’s characteristics and comorbidities in relation to the agent’s side effects and contraindications as detailed in the above section.

Patients should be referred to a movement disorders specialist in cases of resistant tremor, intolerance to oral medications, severe disability, and atypical presentation. Types of tremor known to be poorly responsive to oral medications (eg, head tremor, voice tremor) deserve a specialist evaluation if they contribute significantly to the patient’s morbidity.

The usual specialist treatment of severe voice tremor and head tremor is botulinum toxin injection. Patients with resistant and disabling hand tremor are evaluated for thalamic deep brain stimulation.

Patients with residual disability despite medical and surgical treatment should be referred for occupational therapy. Occupational therapy can improve quality of life through the use of special utensils, pens, computer gadgets, and arm weights, among other devices.

Essential tremor, one of the most common movement disorders, affects about 4% of adults 40 years of age and older.¹ It is often referred to as familial tremor in patients with a family history of tremor. It has also been called benign tremor to differentiate it from tremor associated with neurodegenerative diseases, particularly Parkinson disease, but this condition is certainly not benign, as it can cause substantial functional impairment and difficulties with routine activities of daily living. The terms “essential” and “idiopathic” refer to the primary nature of the disorder and differentiate it from tremor that is a feature of a distinct neurologic entity or is secondary to a metabolic disease or drug therapy.

Successful management entails exclusion of secondary causes and careful selection of drug therapy. To date, there is no cure for essential tremor; all currently available treatments are purely symptomatic.

In this review, we outline the major diagnostic and therapeutic principles of managing essential tremor, indications for referral to specialists, and alternative and advanced therapeutic options.

CLINICAL PICTURE

Tremor is defined as rhythmic to-and-fro movement in any body part. It can be slow or fast, and its amplitude can be large and coarse, or small or even “fine.” It can appear at rest, with action, or during a sustained posture. In contrast to parkinsonian tremor (which presents mainly at rest), essential tremor is typically but not exclusively postural, kinetic, or both.

Postural tremor refers to tremor seen when the patient holds the affected limb (commonly the arm) unsupported against gravity. Kinetic tremor refers to tremor that appears with active movements. This is often demonstrated clinically by the finger-nose-finger test. Patients with essential tremor commonly have both postural and kinetic tremor.

The tremor commonly involves the arms, hands, and fingers.² Less commonly, it involves the head, the lips, the tongue, the legs, and the voice. In contrast to parkinsonian tremor, which typically affects one side of the body first, bilateral involvement is the general rule in essential tremor. However, one side of the body may be affected first, or may be more affected than the other. The frequency of the tremor ranges from 4 to 12 Hz (ie, beats per second).

The tremor usually starts in middle age and progresses slowly over time,³ but onset in old age or childhood is also possible.⁴ Both sexes are equally affected.

The tremor usually gets worse with anxiety, stress, and caffeine intake. It usually gets temporarily better with the consumption of small amounts of alcohol.

The functional impact of essential tremor is judged by its effect on different daily activities, especially writing, eating, drinking, dressing, manual work, and household chores.

In addition to motor dysfunction, the tremor can also have a significant psychological impact on the patient, because it usually gets worse in social situations.

Although it has long been thought that tremor is the sole neurologic sign of essential tremor, recent studies have shown that many patients have additional subtle findings, such as mild gait difficulty,⁵ slight incoordination,⁶ mild cognitive impairment,⁷ and decreased hearing,⁸ and are more likely to have anxiety and social phobia.⁹

Although different studies have varied in their findings, it is generally thought that about 50% of patients with essential tremor have a positive family history, often in a first-degree relative, suggesting autosomal dominant inheritance with variable penetrance.^10,11 Polygenetic and sporadic variants are also common.

DIFFERENTIAL DIAGNOSIS

Resting tremor

Resting tremor is typically an extrapyramidal sign and, when accompanied by rigidity and bradykinesia, is often part of a parkinsonian syndrome. It is most pronounced at rest when the affected body part is fully supported and stationary. The tremor tends to improve with action or posture. It usually has a “pill-rolling” character and, as mentioned, is associated with other extrapyramidal signs, such as rigidity, slowness, and, later on, postural instability.

About 20% of patients with essential tremor have resting tremor. These patients usually suffer from severe or long-standing disease.¹² However, the resting element in these cases is often milder than the postural and kinetic components, and it is typically not associated with other extrapyramidal signs. Also, some patients may have both essential tremor and Parkinson disease.¹³

Intentional tremor

Pure intentional tremor is usually seen with cerebellar pathology, which includes tumors, stroke, multiple sclerosis, trauma, and spinocerebellar degeneration. The amplitude of this type of tremor increases as the affected limb approaches the final target. It can best be demonstrated clinically by the finger-nose-finger test. The frequency of intentional tremor is slow (2 to 4 Hz) and is usually associated with other cerebellar signs, such as dysmetria, decomposition, rebound, and dysdiadochokinesia (ie, the inability to perform rapid alternating movements in a smooth and coordinated manner).

About 50% of patients with essential tremor have an intentional component to their tremor,⁶ or it can be mildly present in the form of a slight gait difficulty. However, in essential tremor, other features of cerebellar dysfunction are either absent or only very slight.

 

 

Secondary causes of postural-kinetic tremor

Enhanced physiologic tremor. A very mild postural tremor is present in almost all people and is considered “physiologic” since it has almost no clinical significance. This type of tremor is often invisible, but when “enhanced,” it can be visually demonstrated by placing a piece of paper over the stretched hands and watching the ripple from the paper.

Certain conditions can aggravate this physiologic tremor and can make it symptomatic. Common causes include anxiety, sleep deprivation, hypoglycemia, hyperthyroidism, pheochromocytoma, serotonin syndrome, and carcinoid syndrome.

Metabolic tremor. Hyperammonemia can cause tremor in patients with hepatic encephalopathy, and uremia can cause tremor in patients with renal failure. These metabolic conditions classically result in “flappy” tremor (asterixis), a special form of postural tremor characterized by jerking movements with high amplitude. It is best seen when the patient stretches out the arms and extends the wrists as if trying to stop traffic. But even though it may look like tremor, asterixis is thought to be a form of “negative” myoclonus.

Drug-related tremor. Postural-kinetic tremor can be induced by drugs, including lithium (Lithobid), valproate (Depakote), amiodarone (Cordarone), central nervous system stimulants, beta agonists (including inhalers), and some antidepressants. Tremor can also occur with alcohol or sedative withdrawal.

Psychogenic tremor. Tremor can be seen as part of a somatoform disorder commonly referred to as conversion disorder or conversion reaction. Psychogenic tremor is characterized by acute onset, commonly following a psychosocial stressor; it is often atypical, variable in frequency, amplitude, and body-part involvement, and it can readily be interrupted on examination by distracting the patient.

Neurologic disorders. The postural and kinetic elements of essential tremor may also be seen in the following neurologic conditions:

• Holmes (rubral) tremor, a combination of resting, postural, kinetic, and intentional tremor of low frequency and high amplitude. It usually has a proximal component and is often unilateral. It commonly is due to a lesion that involves the brainstem, eg, red nucleus, inferior olive, cerebellum, or thalamus. Common causes include stroke, prolonged hypoxia, and head trauma (including closed-head trauma with negative imaging). This type of tremor is usually associated with ataxia.¹⁴
• Dystonic tremor is predominantly postural and is associated with abnormal dystonic posturing of the affected body part, commonly the head, hands, or feet. Unlike the rhythmic oscillations of essential tremor, dystonic tremor is often irregular in rhythm.
• Multiple sclerosis can present with a combination of postural, kinetic, and intentional tremor. Patients usually have a clear history of recurrent neurologic deficits and show a combination of pyramidal, cerebellar, and sensory signs on examination consistent with multiple sclerosis.¹⁵
• Neuropathic tremor is seen in a small proportion of patients with peripheral neuropathy, especially demyelinating neuropathy.¹⁶ The tremor is usually posturalkinetic and is associated with signs of neuropathy, such as a glove-and-stocking pattern of hypoesthesia, reduced reflexes, and sensory ataxia (including intentional tremor when the eyes are closed).
• Posttraumatic tremor can occur after severe or even mild head trauma, especially in children. It is commonly rubral, but other types have been reported, including a presentation resembling essential tremor.¹⁷
• Monosymptomatic or isolated tremor. A number of conditions related to essential tremor with location-specific or task-specific tremor have been described. These rare conditions historically have been classified as “possible essential tremor” or “essential tremor variants” but are now considered separate entities. These include task-specific tremor (eg, writing tremor), isolated head tremor, isolated voice tremor, and orthostatic tremor (tremor in the legs and trunk upon standing in place, but not when sitting or walking).^18,19

DIAGNOSIS IS CLINICAL

Essential tremor is a clinical diagnosis. After a thorough review of the medical history and medication exposures, laboratory and imaging tests may be ordered to rule out a secondary cause. A complete metabolic panel, including blood glucose and thyroid-stimulating hormone levels, is usually sufficient. Brain imaging or other imaging is ordered for patients with an atypical presentation.

TREATMENT IS SYMPTOMATIC

Treatment of essential tremor is symptomatic. Several drugs of different pharmacologic classes can reduce the severity of the tremor and improve function.

Choosing the appropriate treatment depends on the type of tremor and the presence of associated conditions. The response to treatment and the development of side effects guide further adjustments. The following is a brief description of the available antitremor agents.

FIRST-LINE AGENTS

Propranolol

Propranolol (Inderal), a nonselective beta blocker, is the most widely used antitremor drug and the only agent approved by the US Food and Drug Administration for essential tremor. It should be started at a low dose and titrated upward gradually. The usual starting dose is 10 mg three times daily. The average effective dose is 120 mg daily. The dose can be increased up to 320 mg if needed and tolerated.

Sustained-release preparations are equally effective and are given as a single daily dose to improve compliance.²⁰

Propranolol improves tremor in 50% to 70% of patients with essential tremor and achieves an average tremor reduction of 50% to 60%.^1,21–25 Side effects include bronchoconstriction, bradycardia, hypotension, depression, impotence, fatigue, and gastrointestinal disturbances.

Other beta-blockers, such as nadolol (Corgard) and timolol, are also effective against tremor but are less potent than propranolol.^26,27 The selective beta-1-blocker metoprolol (Lopressor) may be effective and has fewer noncardiac side effects than propranolol.²⁸ It can be used in patients who discontinue propranolol because of adverse effects. Atenolol (Tenormin) and pindolol (Visken) have little or no effect on tremor.²⁹

A good candidate for propranolol therapy in essential tremor is:

• A patient with no known contraindication to propranolol
• A patient with hypertension, coronary heart disease, or tachyarrhythmia
• A patient with anxiety or social phobia.

Absolute contraindications to propranolol are:

• Moderate to severe bronchial asthma
• Significant bradycardia or heart block
• Symptomatic hypotension
• End-stage heart failure
• Concurrent use of a calcium channel blocker.

Relative contraindications are:

• Wheezing (eg, chronic obstructive pulmonary disease)
• Depression
• Diabetes mellitus in a patient more prone to hypoglycemia (propranolol masks the warning signs of hypoglycemia)
• Reduced sexual potency in a male patient.

 

 

Primidone

Primidone (Mysoline) is an antiepileptic drug structurally similar to barbiturates. Its antitremor effect is equal to that of propranolol, though some studies suggest it is slightly more efficacious.^30,31

It should be started at a low dose, ie, 25 mg once daily at bedtime. The dose should then be increased gradually until satisfactory and tolerable tremor control is achieved. Most patients respond to doses of around 250 mg per day.^1,22,24–25 The dose can be increased if needed and tolerated.

Primidone reduces tremor by about 50% to 60%.^1,22,24–25 Side effects include sedation, dizziness, fatigue, nausea, and depression, as well as ataxia and confusion in severe cases.

A good candidate for primidone in essential tremor is:

• A patient with no known contraindication to primidone
• A patient with contraindications to propranolol
• A younger patient
• A patient with epilepsy.

Absolute contraindications to primidone include:

• Confusion or dementia
• Oral anticoagulant therapy with difficulty controlling the International Normalized Ratio (primidone is a potent enzyme inducer).

Relative contraindications to primidone in essential tremor are:

• Depression
• Alcohol abuse
• Ongoing therapy with sedating drugs
• Ataxia or vertigo.

SECOND-LINE AGENTS

Other antiepileptics

Topiramate (Topamax) is a broad-spectrum antiepileptic shown to be significantly effective against essential tremor.³² It is usually started at a single daily dose of 25 mg and increased gradually to the most effective dose, usually around 300 mg.

Side effects include reduced appetite, weight loss, cognitive dysfunction, and paresthesia.

Favorable candidates include patients who are epileptic or overweight. Contraindications include cognitive impairment and low body weight. It is also not recommended in children so as to avoid any possible negative effect on cognitive development. In rare cases, topiramate has been reported to cause significant visual disturbances.

Gabapentin (Neurontin) is an antiepileptic that is now more often used as a symptomatic treatment for neuropathic pain. Studies have suggested a beneficial effect on essential tremor,^33,34 but some investigators have questioned its efficacy.³⁵

Like other antitremor agents, it should be started at a low dose, ie, around 300 mg, and escalated gradually until the tremor is controlled. The usual effective dose is 1,200 mg.

Gabapentin is generally well tolerated, and side effects such as dizziness, drowsiness, sedation, and unsteadiness are rare and usually mild.

The favorable candidate is a patient with associated neuropathy or multiple comorbidities. Gabapentin has also been reported to alleviate neuropathic tremor.

Contraindications are minimal and include intolerability or hypersensitivity to the drug. It also should be avoided in patients at a high risk of falling.

Levetiracetam (Keppra) is a novel antiepileptic effective against partial seizures. Studies have shown contradictory results regarding its antitremor effect. One double-blind, placebo-controlled study demonstrated significant reduction in essential tremor with 1,000 mg of levetiracetam.³⁶ However, its effect on tremor is believed to be short-lived, and some studies argue against its efficacy.³⁷ It has a favorable side-effect profile and is generally very well tolerated. It can be used as an adjunct to other antitremor agents and is preferred for patients with coexisting partial seizures or myoclonus.

Benzodiazepines. Minor tranquilizers are often used to control tremor, especially in coexisting anxiety or insomnia. Alprazolam (Xanax) is the one most widely used for this indication.³⁸ It can be started in a dose of 0.25 mg once at bedtime and increased gradually up to 0.75 to 2 mg. Clonazepam (Klonopin) is particularly useful for orthostatic tremor, a variant of essential tremor characterized by tremor of the legs and trunk upon standing.³⁹

Common side effects of benzodiazepines include sedation, cognitive dysfunction, hypotension, respiratory inhibition, and addiction after prolonged use. In the elderly, they can lead to confusion and disinhibition and can increase the risk of falling. They should be avoided in the elderly and in alcoholic patients and those with a high risk of substance abuse.

Stopping benzodiazepines should be done gradually to avoid withdrawal symptoms, including aggravation of tremor.

THIRD-LINE AGENTS

Clozapine

Clozapine (Clozaril) is a novel antipsychotic drug with no extrapyramidal side effects. It has been reported effective in essential tremor and drug-induced tremor,^40,41 but the results of these early studies have not been confirmed.

Clozapine is started as a single daily dose of 12.5 mg and is increased up to 75 mg or 100 mg. It is an attractive option for patients with coexisting psychosis, bipolar disorder, or chorea. Its main side effects are sedation, salivation, weight gain, hypertension, diabetes, and seizures.

One especially serious side effect is agranulocytosis. This potentially fatal effect is rare, occurring in about 1.3% of patients receiving this drug. Weekly monitoring of the white blood cell count is mandated during treatment with clozapine, and this has made clozapine a less attractive option for the routine treatment of essential tremor.

Mirtazapine

Mirtazapine (Remeron) is a novel antidepressant widely used in Parkinson disease as both an antidepressant and a sleeping aid. Case studies have reported efficacy in both essential tremor and parkinsonian tremor,⁴² but controlled studies have not confirmed this.⁴³ Mirtazapine is a reasonable option in patients with coexisting depression or insomnia. It is usually given as a single bedtime dose of 15 to 30 mg.

Other drugs

Studies of other agents for the treatment of essential tremor—eg, carbonic anhydrase enzyme inhibitors, calcium channel blockers, isoniazid (Tubizid), clonidine (Catapres), phenobarbital, and theophylline—have yielded highly contradictory results. Thus, they are not recommended as first- or second-line agents for essential tremor.

SPECIALTY-LEVEL CARE

When essential tremor does not respond to drug therapy or the patient cannot tolerate drug therapy, the patient should be referred to a center specializing in movement disorders for more advanced treatment options, ie, botulinum toxin injection and deep brain stimulation surgery.

Botulinum toxin

Botulinum toxin type A has been studied for the treatment of essential tremor with variable degrees of success. It has been effective in reducing hand tremor in essential tremor, but without a concomitant improvement in functional disability.⁴⁴ This limited functional improvement has been attributed to the development of muscle weakness after injection of the neurotoxin. This has also raised questions about unintentional unblinding when interpreting study results. Therefore, most clinicians restrict its use to focal forms of tremor such as voice tremor,⁴⁵ head tremor, and task-specific tremor.

Side effects are limited and temporary and include muscle weakness, pain at the injection site, dysphagia (when injected for head or voice tremor), and a breathy vocal quality (when injected for voice tremor). Botulinum toxin injection is the treatment of choice for focal dystonia, and therefore would be a good option for dystonic tremor.

Thalamic deep brain stimulation

This technique involves stereotactic implantation of a stimulation lead in the ventral intermediate nucleus of the thalamus. The lead connects via a subcutaneous wire to an intermittent pulse generator, implanted subcutaneously in the infraclavicular region. The stimulation lead produces continuous stimulation of the ventralis intermedius nucleus that is functionally equal to lesional surgery, thus antagonizing the relay of tremor signals at the thalamus.

The battery of the pulse generator must be replaced every 4 to 7 years depending on usage and stimulation parameters. Battery replacement can be performed with minor surgery at the infraclavicular region.

Thalamic deep brain stimulation is indicated for patients with severe, disabling essential tremor who have tremor resistant to drug therapy or who cannot tolerate drug therapy.

The procedure has been shown to provide benefit in 90% of patients, with more than an 80% improvement in tremor severity and functional impact.^46–49 Deep brain stimulation is effective against tremor affecting parts of the body other than the limbs, including the head; an exception to this is voice tremor, which usually does not improve dramatically. The procedure can be done unilaterally or bilaterally, depending on symptoms. Patients with asymmetrical tremor and those at risk of side effects can undergo unilateral surgery. Bilateral treatment is recommended for patients with symmetric tremor or significant head tremor, or who are young and healthy.

Surgical risks include brain hemorrhage and infection. Side effects of the stimulation include paresthesias, paresis, imbalance, dysarthria, and, in rare cases, dysphagia.

CHOOSING THE BEST MANAGEMENT PLAN FOR YOUR PATIENT

The choice of treatment may be challenging, given the multiple treatment options and the variability of tremor severity from one patient to another. The following guidelines can be used to help make this decision.

All patients should be advised to reduce caffeine intake, to have sufficient hours of sleep, and to avoid stressful situations.

Patients with minor, nondisabling tremor can be left untreated if the tremors are not bothersome or if the patient prefers not to pursue active treatment.

In patients who have bothersome tremor only when anxious or in certain social situations, give propranolol or alprazolam (or both) to be taken as needed. Relaxation techniques and meditation are also useful for these patients.

Patients with constant bothersome tremor should be started on either propranolol or primidone based on the patient’s profile and propensity to develop side effects from each of these drugs. The dosing should be optimized gradually according to the patient’s response and the drug’s tolerability.

If essential tremor is not sufficiently controlled with one first-line agent (propranolol or primidone), try combining the two first-line agents if the patient finds it tolerable.

A second-line agent can be added to either of the first-line agents or to the combination of both if tremor control is not yet sufficient. A second-line or third-line agent can also be used as the primary treatment if both first-line agents are contraindicated or intolerable. Combining two or more second- and third-line agents is another option. The choice of second- or third-line agent should be guided by the patient’s characteristics and comorbidities in relation to the agent’s side effects and contraindications as detailed in the above section.

Patients should be referred to a movement disorders specialist in cases of resistant tremor, intolerance to oral medications, severe disability, and atypical presentation. Types of tremor known to be poorly responsive to oral medications (eg, head tremor, voice tremor) deserve a specialist evaluation if they contribute significantly to the patient’s morbidity.

The usual specialist treatment of severe voice tremor and head tremor is botulinum toxin injection. Patients with resistant and disabling hand tremor are evaluated for thalamic deep brain stimulation.

Patients with residual disability despite medical and surgical treatment should be referred for occupational therapy. Occupational therapy can improve quality of life through the use of special utensils, pens, computer gadgets, and arm weights, among other devices.

A 54-year-old woman with a 1-month history of progressive weakness was transported to the emergency department of a local hospital when a family member found her unresponsive. Before this event, the patient had said she had been feeling tired and cold and looking pale for several weeks.

In the emergency department, her temperature was low. Cableomputed tomography (CT) of the head showed a 1.4-cm hyperdense extraaxial mass. Imaging of the chest showed focal consolidations within the anterior segment of the right upper lobe and the left and right lower lobes.

A urine toxicology screen was positive for acetaminophen (Tylenol), opiates, and benzodiazepines. She was given three doses of naloxone (Narcan), which raised her level of arousal; however, she later became obtunded again and was intubated and transferred to Cleveland Clinic.

A new CT scan of the head confirmed a small left temporal, extradural, calcified lesion with no mass effect or overt bleeding; it appeared most compatible with a solitary calcified meningioma—a likely benign finding.

Her medical history includes hypertension, type 2 diabetes (controlled with diet), and osteoarthritis of the spine. In 1999, she had undergone a hysterectomy that necessitated a blood transfusion. She has never smoked tobacco and does not consume alcohol or use illicit drugs. In the past she worked as a nurse’s aid in a nursing home. However, for the past several years she has stayed at home. Her only avocation of note is gardening.

Initial physical examination

The patient is intubated and sedated. Her temperature is 35.3°C (95.5°F), blood pressure 122/81 mm Hg, heart rate 83 beats per minute, and respiratory rate 14 on assist-controlled ventilator settings with an Fio₂ of 100% and a positive end-expiratory pressure of 5 cm H₂O.

Her pupils are round, equal, and reactive to light. Her face is symmetric and notable for hirsutism over the chin. Her neck is supple and without lymphadenopathy or thyromegaly.

Rhonchi can be heard at both lung bases. She has normal bowel sounds, and her abdomen is soft and nondistended, with no masses or palpable hepatosplenomegaly. She has no pedal edema on either side, and no clubbing or cyanosis. Her skin is intact, without rashes, lesions, or tattoos. She is able to withdraw from painful stimuli in all four extremities.

INITIAL TESTS PROVIDE A CLUE

1. Which of the following is the likely cause of this patient’s pancytopenia?

• Folate deficiency
• Gastrointestinal bleeding secondary to colon cancer
• 
  Acute myeloid leukemia
• Paroxysmal nocturnal hemoglobinuria
• Myelophthisis
• Other

Causes of pancytopenia are listed in Table 2.

Folate deficiency

Folate is necessary for thymidylate synthesis, a rate-limiting step in DNA synthesis. The minimum daily requirement for dietary folate intake is 50 μg.

Severe deficiency of folate has been reported to cause pancytopenia in alcoholics.¹ Abuse of alcohol leads to an abrupt decrease in serum folate (within 2 to 4 days of ceasing intake of proper amounts of folate, as in an alcoholic binge) by inhibiting its absorption in the proximal jejunum as well as its metabolism in the liver.² The resulting folate deficiency, if sustained, can develop into megaloblastosis in 5 to 10 weeks.

The duration of weakness and pallor reported by this patient would raise suspicion of folate deficiency if she had a history of malnutrition or of alcohol abuse, but she has neither. Further, her mean corpuscular volume is 82.5 fL, red blood cell folate 391 ng/mL (reference range 257–800 ng/mL), and serum vitamin B₁₂ 1,886 pg/mL (22–700 pg/mL), and she has no macro-ovalocytes or hypersegmented neutrophils on a peripheral blood smear. This makes folate or vitamin B₁₂ deficiency less likely.

Gastrointestinal bleeding due to colon cancer

Iron-deficiency anemia, hematochezia, melena, a change in bowel habits, and abdominal pain may be manifestations of colon cancer. Cancers of the colon originate from adenomatous polyps arising from the colonic mucosa.

The quantity of occult blood loss depends on the site of the tumor. Patients with tumors in the cecum or ascending colon lose an average of 9 mL/day, whereas those with tumors in the transverse, descending, or sigmoid colon or rectum lose less than 2 mL/day.³

Pertinent laboratory findings in iron-deficiency anemia are a low iron concentration, a low transferrin saturation, a depleted serum ferritin, and a normal to high total iron-binding capacity. An initial microcytic normochromic anemia eventually progresses to a microcytic hypochromic anemia that has a tendency to increasingly demonstrate anisocytosis and poikilocytosis.

Our patient’s symptoms, signs, and laboratory values (with normocytic normochromic anemia) are inconsistent with symptomatic colon cancer leading to iron-deficiency anemia.

 

 

Acute myeloid leukemia

Acute myeloid leukemia generally manifests with symptoms related to pancytopenia, with weakness and fatigability being the most common.⁴

In this condition, genetic alterations in hematopoietic precursor cells result in reduced differentiation capacity and accumulation of leukemic blasts in the bone marrow, peripheral blood, and other tissues.

Peripheral blood analysis usually reveals normocytic normochromic anemia with blasts. To establish a diagnosis of acute myeloid leukemia, one must observe at least 20% myeloblasts in the blood, the bone marrow, or both.

No blasts are seen on our patient’s peripheral blood smear, making acute myeloid leukemia less likely.

Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria is a possibility in the setting of intravascular hemolytic anemia, bone marrow failure, and thrombosis.

These processes are due to a defect in the glycosyl phosphatidyl inositol (GPI) anchor caused by an abnormality in the PIG-A gene. Partial or complete absence of the GPI anchor allows for activation of complement-mediated hemolysis. A diminished rate of hematopoiesis is presumably responsible for reticulocytopenia, granulocytopenia, or thrombocytopenia, though reticulocytosis can also be seen.^5,6 The highly thrombogenic state is believed to occur because of microparticles rich in phosphatidylserine.⁷

Our patient’s peripheral smear has rare fragmented red blood cells and lacks teardrop red cells. Although paroxysmal nocturnal hemoglobinuria does not have characteristic morphologic features in the peripheral blood, there are no signs of thrombosis in our patient. Her lactate dehydrogenase level is 395 U/L (reference range 100–220 U/L), and her haptoglobin level is less than 20 mg/dL (33–246). These findings could indicate a low level of intravascular hemolysis.

Myelophthisis

Myelophthisis refers to any disorder in which an abnormal cell process invades the bone marrow, damaging hematopoietic tissue. These processes include neoplastic diseases, storage disorders, and a variety of infections. A decrease in all three cell types may result, depending on the severity of invasion. Documented infectious causes include hepatitis viruses, Epstein-Barr virus, human immunodeficiency virus (HIV), mycobacteria, and fungi.

Our patient’s condition is likely due to a marrow-based process of uncertain etiology. In myelophthisic processes, one may see teardrop red cells, which are not seen in this patient’s smear. However, on her chest imaging, the finding of focal consolidations within the anterior segment of the right upper lobe and both lower lobes raises suspicion of an infectious cause.

CASE CONTINUED: SHE UNDERGOES DIAGNOSTIC TESTING

Let us recap some of the laboratory studies that document the extent of our patient’s pancytopenia and the pattern of her anemia:

• Hemoglobin 10.2 g/dL (reference range 11.5–15.5 g/dL)
• Platelet count 27 × 10⁹/L (150–400)
• Leukopenia with profound T-cell lymphopenia
• Iron 59 μg/dL (30–140)
• Total iron-binding capacity 110 μg/dL (210–415)
• Ferritin 3,004 ng/mL (18–300)
• Transferrin saturation 54% (11%–46%).

2. Which of the following would be the best test to obtain next?

• Bone marrow examination
• Blood cultures
• Tuberculin skin test
• Liver biopsy
• Positron emission tomography and CT

Our patient has unexplained pancytopenia. While all the tests listed above might shed light on her condition, a bone marrow examination would be the best test to obtain next.

Urine histoplasma antigen studies are positive at greater than 39 ng/mL (normal 0, low positive < 0.6–3.9, moderate positive 4.0–19.9, high positive 20–39 ng/mL). A culture of the marrow subsequently grows this organism.

3. Which of the following tests would establish a definitive diagnosis in this patient?

• Methenamine silver stain of the marrow
• Serum antibody testing
• Fungal culture
• Peripheral blood smear
• Carbolfuchsin stain of marrow
• Urine histoplasma antigen

A prompt diagnosis is critical in patients with acute pulmonary histoplasmosis or progressive disseminated histoplasmosis because early treatment may shorten the clinical course and length of treatment and, in cases of disseminated histoplasmosis, prevent death.^8–10

Histopathologic examination of the bone marrow gives the most rapid results, although biopsy to obtain the tissue is invasive. It can give a definitive diagnosis if it reveals the typical 2- to 4-μm yeast structures of H capsulatum. These are observed on an aspirate smear of the patient’s bone marrow biopsy (Figure 1) and can be confirmed by methenamine silver or periodic acid-Schiff staining of the tissue.

Antibody detection is less practical because the antibodies take 2 to 6 weeks after infection to form.¹¹ Also, it is less useful in cases of disseminated infection because many of these patients are immunosuppressed.

Fungal culture remains the gold standard diagnostic test for histoplasmosis. However, results may take up to 1 month and may be falsely negative in less severe cases.

Histoplasma antigen testing is of greater utility in patients with severe disease, including cases of disseminated histoplasmosis. Rates of antigen detection approach 90% in urine specimens from non-AIDS patients with disseminated infection.¹² The urine assay has a greater sensitivity and specificity than the serum assay. The rate of detection is lower (ie, around 82%) in patients with acute pulmonary histoplasmosis when both the serum and urine specimens are tested.¹³

The immunoassay for histoplasma antigen is particularly useful for monitoring the response to therapy. Antigen levels should be measured before treatment is started and at 2 weeks, 1 month, and then approximately every 3 months during therapy.¹⁴ If the treatment is effective, antigens should decline by at least 20% in the first month of treatment and by another 20% in each of the following 3-month intervals. Antigen testing should be done every 3 months until a negative antigen level is achieved. The antigen level should also be followed for at least 6 months after treatment has stopped.¹⁴

HISTOPLASMA IS INHALED

H capsulatum is the cause of one of the most common pulmonary and systemic mycotic infections in the world, with hundreds of thousands of new cases annually. In areas where the soil is contaminated by bird or bat guano, the fungus is inhaled, resulting in an asymptomatic or a self-limiting influenza-like syndrome in an immunocompetent individual.¹⁵

An antigen-specific CD4⁺ T lymphocytemediated immunity occurs. The immune response of the host is thought to be fungistatic rather than fungicidal, resulting in a persistent inactive infection capable of reactivation in the presence of a host-pathogen imbalance.¹⁶

Most infections are asymptomatic or self-limited. For every 2,000 acute infections there is one that results in severe and progressive dissemination, usually in an immunocompromised host.^17,18

TREATMENT OF HISTOPLASMOSIS

4. What is the appropriate initial choice of treatment for a severe case of disseminated histoplasmosis?

• Amphotericin B in a lipid complex formulation (Abelcet)
• Itraconazole (Sporanox)
• Fluconazole (Diflucan)
• Ketoconazole (Nizoral)

Untreated, acute disseminated histoplasmosis can progress over a period of 2 to 12 weeks, ultimately killing the patient.^17,19

The leading therapies include amphotericin B in a lipid formulation and azole drugs, in particular itraconazole. Fluconazole and ketoconazole are not first-line options in severe cases because they are less predictably effective, and ketoconazole has a higher rate of side effects.^20–23 The current recommendation is to treat severely ill hospitalized patients with one of the liposomal formulations or the lipid complex formulation of amphotericin B. Itraconazole is used for patients who have mild to moderate symptoms and as a step-down therapy in patients who improve after initial use of amphotericin B.

CASE CONCLUDED: THE PATIENT RECOVERS

At the time of the initial patient encounter, there was no history of or obvious cause of immunosuppression in this patient. She was found to be HIV-negative and was subsequently diagnosed with “profound immunosuppression of unknown etiology” resulting in a low CD4 count.

The patient receives trimethoprim-sulfamethoxazole (Bactrim, Septra) and azithromycin (Zithromax) for prophylaxis against Pneumocystis carinii pneumonia and Mycobacterium avium intracellulare infection. Two months after the hospitalization, she recalls being at a corn maze 1 month before becoming ill.

A 54-year-old woman with a 1-month history of progressive weakness was transported to the emergency department of a local hospital when a family member found her unresponsive. Before this event, the patient had said she had been feeling tired and cold and looking pale for several weeks.

In the emergency department, her temperature was low. Cableomputed tomography (CT) of the head showed a 1.4-cm hyperdense extraaxial mass. Imaging of the chest showed focal consolidations within the anterior segment of the right upper lobe and the left and right lower lobes.

A urine toxicology screen was positive for acetaminophen (Tylenol), opiates, and benzodiazepines. She was given three doses of naloxone (Narcan), which raised her level of arousal; however, she later became obtunded again and was intubated and transferred to Cleveland Clinic.

A new CT scan of the head confirmed a small left temporal, extradural, calcified lesion with no mass effect or overt bleeding; it appeared most compatible with a solitary calcified meningioma—a likely benign finding.

Her medical history includes hypertension, type 2 diabetes (controlled with diet), and osteoarthritis of the spine. In 1999, she had undergone a hysterectomy that necessitated a blood transfusion. She has never smoked tobacco and does not consume alcohol or use illicit drugs. In the past she worked as a nurse’s aid in a nursing home. However, for the past several years she has stayed at home. Her only avocation of note is gardening.

Initial physical examination

The patient is intubated and sedated. Her temperature is 35.3°C (95.5°F), blood pressure 122/81 mm Hg, heart rate 83 beats per minute, and respiratory rate 14 on assist-controlled ventilator settings with an Fio₂ of 100% and a positive end-expiratory pressure of 5 cm H₂O.

Her pupils are round, equal, and reactive to light. Her face is symmetric and notable for hirsutism over the chin. Her neck is supple and without lymphadenopathy or thyromegaly.

Rhonchi can be heard at both lung bases. She has normal bowel sounds, and her abdomen is soft and nondistended, with no masses or palpable hepatosplenomegaly. She has no pedal edema on either side, and no clubbing or cyanosis. Her skin is intact, without rashes, lesions, or tattoos. She is able to withdraw from painful stimuli in all four extremities.

INITIAL TESTS PROVIDE A CLUE

1. Which of the following is the likely cause of this patient’s pancytopenia?

• Folate deficiency
• Gastrointestinal bleeding secondary to colon cancer
• 
  Acute myeloid leukemia
• Paroxysmal nocturnal hemoglobinuria
• Myelophthisis
• Other

Causes of pancytopenia are listed in Table 2.

Folate deficiency

Folate is necessary for thymidylate synthesis, a rate-limiting step in DNA synthesis. The minimum daily requirement for dietary folate intake is 50 μg.

Severe deficiency of folate has been reported to cause pancytopenia in alcoholics.¹ Abuse of alcohol leads to an abrupt decrease in serum folate (within 2 to 4 days of ceasing intake of proper amounts of folate, as in an alcoholic binge) by inhibiting its absorption in the proximal jejunum as well as its metabolism in the liver.² The resulting folate deficiency, if sustained, can develop into megaloblastosis in 5 to 10 weeks.

The duration of weakness and pallor reported by this patient would raise suspicion of folate deficiency if she had a history of malnutrition or of alcohol abuse, but she has neither. Further, her mean corpuscular volume is 82.5 fL, red blood cell folate 391 ng/mL (reference range 257–800 ng/mL), and serum vitamin B₁₂ 1,886 pg/mL (22–700 pg/mL), and she has no macro-ovalocytes or hypersegmented neutrophils on a peripheral blood smear. This makes folate or vitamin B₁₂ deficiency less likely.

Gastrointestinal bleeding due to colon cancer

Iron-deficiency anemia, hematochezia, melena, a change in bowel habits, and abdominal pain may be manifestations of colon cancer. Cancers of the colon originate from adenomatous polyps arising from the colonic mucosa.

The quantity of occult blood loss depends on the site of the tumor. Patients with tumors in the cecum or ascending colon lose an average of 9 mL/day, whereas those with tumors in the transverse, descending, or sigmoid colon or rectum lose less than 2 mL/day.³

Pertinent laboratory findings in iron-deficiency anemia are a low iron concentration, a low transferrin saturation, a depleted serum ferritin, and a normal to high total iron-binding capacity. An initial microcytic normochromic anemia eventually progresses to a microcytic hypochromic anemia that has a tendency to increasingly demonstrate anisocytosis and poikilocytosis.

Our patient’s symptoms, signs, and laboratory values (with normocytic normochromic anemia) are inconsistent with symptomatic colon cancer leading to iron-deficiency anemia.

 

 

Acute myeloid leukemia

Acute myeloid leukemia generally manifests with symptoms related to pancytopenia, with weakness and fatigability being the most common.⁴

In this condition, genetic alterations in hematopoietic precursor cells result in reduced differentiation capacity and accumulation of leukemic blasts in the bone marrow, peripheral blood, and other tissues.

Peripheral blood analysis usually reveals normocytic normochromic anemia with blasts. To establish a diagnosis of acute myeloid leukemia, one must observe at least 20% myeloblasts in the blood, the bone marrow, or both.

No blasts are seen on our patient’s peripheral blood smear, making acute myeloid leukemia less likely.

Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria is a possibility in the setting of intravascular hemolytic anemia, bone marrow failure, and thrombosis.

These processes are due to a defect in the glycosyl phosphatidyl inositol (GPI) anchor caused by an abnormality in the PIG-A gene. Partial or complete absence of the GPI anchor allows for activation of complement-mediated hemolysis. A diminished rate of hematopoiesis is presumably responsible for reticulocytopenia, granulocytopenia, or thrombocytopenia, though reticulocytosis can also be seen.^5,6 The highly thrombogenic state is believed to occur because of microparticles rich in phosphatidylserine.⁷

Our patient’s peripheral smear has rare fragmented red blood cells and lacks teardrop red cells. Although paroxysmal nocturnal hemoglobinuria does not have characteristic morphologic features in the peripheral blood, there are no signs of thrombosis in our patient. Her lactate dehydrogenase level is 395 U/L (reference range 100–220 U/L), and her haptoglobin level is less than 20 mg/dL (33–246). These findings could indicate a low level of intravascular hemolysis.

Myelophthisis

Myelophthisis refers to any disorder in which an abnormal cell process invades the bone marrow, damaging hematopoietic tissue. These processes include neoplastic diseases, storage disorders, and a variety of infections. A decrease in all three cell types may result, depending on the severity of invasion. Documented infectious causes include hepatitis viruses, Epstein-Barr virus, human immunodeficiency virus (HIV), mycobacteria, and fungi.

Our patient’s condition is likely due to a marrow-based process of uncertain etiology. In myelophthisic processes, one may see teardrop red cells, which are not seen in this patient’s smear. However, on her chest imaging, the finding of focal consolidations within the anterior segment of the right upper lobe and both lower lobes raises suspicion of an infectious cause.

CASE CONTINUED: SHE UNDERGOES DIAGNOSTIC TESTING

Let us recap some of the laboratory studies that document the extent of our patient’s pancytopenia and the pattern of her anemia:

• Hemoglobin 10.2 g/dL (reference range 11.5–15.5 g/dL)
• Platelet count 27 × 10⁹/L (150–400)
• Leukopenia with profound T-cell lymphopenia
• Iron 59 μg/dL (30–140)
• Total iron-binding capacity 110 μg/dL (210–415)
• Ferritin 3,004 ng/mL (18–300)
• Transferrin saturation 54% (11%–46%).

2. Which of the following would be the best test to obtain next?

• Bone marrow examination
• Blood cultures
• Tuberculin skin test
• Liver biopsy
• Positron emission tomography and CT

Our patient has unexplained pancytopenia. While all the tests listed above might shed light on her condition, a bone marrow examination would be the best test to obtain next.

Urine histoplasma antigen studies are positive at greater than 39 ng/mL (normal 0, low positive < 0.6–3.9, moderate positive 4.0–19.9, high positive 20–39 ng/mL). A culture of the marrow subsequently grows this organism.

3. Which of the following tests would establish a definitive diagnosis in this patient?

• Methenamine silver stain of the marrow
• Serum antibody testing
• Fungal culture
• Peripheral blood smear
• Carbolfuchsin stain of marrow
• Urine histoplasma antigen

A prompt diagnosis is critical in patients with acute pulmonary histoplasmosis or progressive disseminated histoplasmosis because early treatment may shorten the clinical course and length of treatment and, in cases of disseminated histoplasmosis, prevent death.^8–10

Histopathologic examination of the bone marrow gives the most rapid results, although biopsy to obtain the tissue is invasive. It can give a definitive diagnosis if it reveals the typical 2- to 4-μm yeast structures of H capsulatum. These are observed on an aspirate smear of the patient’s bone marrow biopsy (Figure 1) and can be confirmed by methenamine silver or periodic acid-Schiff staining of the tissue.

Antibody detection is less practical because the antibodies take 2 to 6 weeks after infection to form.¹¹ Also, it is less useful in cases of disseminated infection because many of these patients are immunosuppressed.

Fungal culture remains the gold standard diagnostic test for histoplasmosis. However, results may take up to 1 month and may be falsely negative in less severe cases.

Histoplasma antigen testing is of greater utility in patients with severe disease, including cases of disseminated histoplasmosis. Rates of antigen detection approach 90% in urine specimens from non-AIDS patients with disseminated infection.¹² The urine assay has a greater sensitivity and specificity than the serum assay. The rate of detection is lower (ie, around 82%) in patients with acute pulmonary histoplasmosis when both the serum and urine specimens are tested.¹³

The immunoassay for histoplasma antigen is particularly useful for monitoring the response to therapy. Antigen levels should be measured before treatment is started and at 2 weeks, 1 month, and then approximately every 3 months during therapy.¹⁴ If the treatment is effective, antigens should decline by at least 20% in the first month of treatment and by another 20% in each of the following 3-month intervals. Antigen testing should be done every 3 months until a negative antigen level is achieved. The antigen level should also be followed for at least 6 months after treatment has stopped.¹⁴

HISTOPLASMA IS INHALED

H capsulatum is the cause of one of the most common pulmonary and systemic mycotic infections in the world, with hundreds of thousands of new cases annually. In areas where the soil is contaminated by bird or bat guano, the fungus is inhaled, resulting in an asymptomatic or a self-limiting influenza-like syndrome in an immunocompetent individual.¹⁵

An antigen-specific CD4⁺ T lymphocytemediated immunity occurs. The immune response of the host is thought to be fungistatic rather than fungicidal, resulting in a persistent inactive infection capable of reactivation in the presence of a host-pathogen imbalance.¹⁶

Most infections are asymptomatic or self-limited. For every 2,000 acute infections there is one that results in severe and progressive dissemination, usually in an immunocompromised host.^17,18

TREATMENT OF HISTOPLASMOSIS

4. What is the appropriate initial choice of treatment for a severe case of disseminated histoplasmosis?

• Amphotericin B in a lipid complex formulation (Abelcet)
• Itraconazole (Sporanox)
• Fluconazole (Diflucan)
• Ketoconazole (Nizoral)

Untreated, acute disseminated histoplasmosis can progress over a period of 2 to 12 weeks, ultimately killing the patient.^17,19

The leading therapies include amphotericin B in a lipid formulation and azole drugs, in particular itraconazole. Fluconazole and ketoconazole are not first-line options in severe cases because they are less predictably effective, and ketoconazole has a higher rate of side effects.^20–23 The current recommendation is to treat severely ill hospitalized patients with one of the liposomal formulations or the lipid complex formulation of amphotericin B. Itraconazole is used for patients who have mild to moderate symptoms and as a step-down therapy in patients who improve after initial use of amphotericin B.

CASE CONCLUDED: THE PATIENT RECOVERS

At the time of the initial patient encounter, there was no history of or obvious cause of immunosuppression in this patient. She was found to be HIV-negative and was subsequently diagnosed with “profound immunosuppression of unknown etiology” resulting in a low CD4 count.

The patient receives trimethoprim-sulfamethoxazole (Bactrim, Septra) and azithromycin (Zithromax) for prophylaxis against Pneumocystis carinii pneumonia and Mycobacterium avium intracellulare infection. Two months after the hospitalization, she recalls being at a corn maze 1 month before becoming ill.

A 54-year-old woman with a 1-month history of progressive weakness was transported to the emergency department of a local hospital when a family member found her unresponsive. Before this event, the patient had said she had been feeling tired and cold and looking pale for several weeks.

In the emergency department, her temperature was low. Cableomputed tomography (CT) of the head showed a 1.4-cm hyperdense extraaxial mass. Imaging of the chest showed focal consolidations within the anterior segment of the right upper lobe and the left and right lower lobes.

A urine toxicology screen was positive for acetaminophen (Tylenol), opiates, and benzodiazepines. She was given three doses of naloxone (Narcan), which raised her level of arousal; however, she later became obtunded again and was intubated and transferred to Cleveland Clinic.

A new CT scan of the head confirmed a small left temporal, extradural, calcified lesion with no mass effect or overt bleeding; it appeared most compatible with a solitary calcified meningioma—a likely benign finding.

Her medical history includes hypertension, type 2 diabetes (controlled with diet), and osteoarthritis of the spine. In 1999, she had undergone a hysterectomy that necessitated a blood transfusion. She has never smoked tobacco and does not consume alcohol or use illicit drugs. In the past she worked as a nurse’s aid in a nursing home. However, for the past several years she has stayed at home. Her only avocation of note is gardening.

Initial physical examination

The patient is intubated and sedated. Her temperature is 35.3°C (95.5°F), blood pressure 122/81 mm Hg, heart rate 83 beats per minute, and respiratory rate 14 on assist-controlled ventilator settings with an Fio₂ of 100% and a positive end-expiratory pressure of 5 cm H₂O.

Her pupils are round, equal, and reactive to light. Her face is symmetric and notable for hirsutism over the chin. Her neck is supple and without lymphadenopathy or thyromegaly.

Rhonchi can be heard at both lung bases. She has normal bowel sounds, and her abdomen is soft and nondistended, with no masses or palpable hepatosplenomegaly. She has no pedal edema on either side, and no clubbing or cyanosis. Her skin is intact, without rashes, lesions, or tattoos. She is able to withdraw from painful stimuli in all four extremities.

INITIAL TESTS PROVIDE A CLUE

1. Which of the following is the likely cause of this patient’s pancytopenia?

• Folate deficiency
• Gastrointestinal bleeding secondary to colon cancer
• 
  Acute myeloid leukemia
• Paroxysmal nocturnal hemoglobinuria
• Myelophthisis
• Other

Causes of pancytopenia are listed in Table 2.

Folate deficiency

Folate is necessary for thymidylate synthesis, a rate-limiting step in DNA synthesis. The minimum daily requirement for dietary folate intake is 50 μg.

Severe deficiency of folate has been reported to cause pancytopenia in alcoholics.¹ Abuse of alcohol leads to an abrupt decrease in serum folate (within 2 to 4 days of ceasing intake of proper amounts of folate, as in an alcoholic binge) by inhibiting its absorption in the proximal jejunum as well as its metabolism in the liver.² The resulting folate deficiency, if sustained, can develop into megaloblastosis in 5 to 10 weeks.

The duration of weakness and pallor reported by this patient would raise suspicion of folate deficiency if she had a history of malnutrition or of alcohol abuse, but she has neither. Further, her mean corpuscular volume is 82.5 fL, red blood cell folate 391 ng/mL (reference range 257–800 ng/mL), and serum vitamin B₁₂ 1,886 pg/mL (22–700 pg/mL), and she has no macro-ovalocytes or hypersegmented neutrophils on a peripheral blood smear. This makes folate or vitamin B₁₂ deficiency less likely.

Gastrointestinal bleeding due to colon cancer

Iron-deficiency anemia, hematochezia, melena, a change in bowel habits, and abdominal pain may be manifestations of colon cancer. Cancers of the colon originate from adenomatous polyps arising from the colonic mucosa.

The quantity of occult blood loss depends on the site of the tumor. Patients with tumors in the cecum or ascending colon lose an average of 9 mL/day, whereas those with tumors in the transverse, descending, or sigmoid colon or rectum lose less than 2 mL/day.³

Pertinent laboratory findings in iron-deficiency anemia are a low iron concentration, a low transferrin saturation, a depleted serum ferritin, and a normal to high total iron-binding capacity. An initial microcytic normochromic anemia eventually progresses to a microcytic hypochromic anemia that has a tendency to increasingly demonstrate anisocytosis and poikilocytosis.

Our patient’s symptoms, signs, and laboratory values (with normocytic normochromic anemia) are inconsistent with symptomatic colon cancer leading to iron-deficiency anemia.

 

 

Acute myeloid leukemia

Acute myeloid leukemia generally manifests with symptoms related to pancytopenia, with weakness and fatigability being the most common.⁴

In this condition, genetic alterations in hematopoietic precursor cells result in reduced differentiation capacity and accumulation of leukemic blasts in the bone marrow, peripheral blood, and other tissues.

Peripheral blood analysis usually reveals normocytic normochromic anemia with blasts. To establish a diagnosis of acute myeloid leukemia, one must observe at least 20% myeloblasts in the blood, the bone marrow, or both.

No blasts are seen on our patient’s peripheral blood smear, making acute myeloid leukemia less likely.

Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria is a possibility in the setting of intravascular hemolytic anemia, bone marrow failure, and thrombosis.

These processes are due to a defect in the glycosyl phosphatidyl inositol (GPI) anchor caused by an abnormality in the PIG-A gene. Partial or complete absence of the GPI anchor allows for activation of complement-mediated hemolysis. A diminished rate of hematopoiesis is presumably responsible for reticulocytopenia, granulocytopenia, or thrombocytopenia, though reticulocytosis can also be seen.^5,6 The highly thrombogenic state is believed to occur because of microparticles rich in phosphatidylserine.⁷

Our patient’s peripheral smear has rare fragmented red blood cells and lacks teardrop red cells. Although paroxysmal nocturnal hemoglobinuria does not have characteristic morphologic features in the peripheral blood, there are no signs of thrombosis in our patient. Her lactate dehydrogenase level is 395 U/L (reference range 100–220 U/L), and her haptoglobin level is less than 20 mg/dL (33–246). These findings could indicate a low level of intravascular hemolysis.

Myelophthisis

Myelophthisis refers to any disorder in which an abnormal cell process invades the bone marrow, damaging hematopoietic tissue. These processes include neoplastic diseases, storage disorders, and a variety of infections. A decrease in all three cell types may result, depending on the severity of invasion. Documented infectious causes include hepatitis viruses, Epstein-Barr virus, human immunodeficiency virus (HIV), mycobacteria, and fungi.

Our patient’s condition is likely due to a marrow-based process of uncertain etiology. In myelophthisic processes, one may see teardrop red cells, which are not seen in this patient’s smear. However, on her chest imaging, the finding of focal consolidations within the anterior segment of the right upper lobe and both lower lobes raises suspicion of an infectious cause.

CASE CONTINUED: SHE UNDERGOES DIAGNOSTIC TESTING

Let us recap some of the laboratory studies that document the extent of our patient’s pancytopenia and the pattern of her anemia:

• Hemoglobin 10.2 g/dL (reference range 11.5–15.5 g/dL)
• Platelet count 27 × 10⁹/L (150–400)
• Leukopenia with profound T-cell lymphopenia
• Iron 59 μg/dL (30–140)
• Total iron-binding capacity 110 μg/dL (210–415)
• Ferritin 3,004 ng/mL (18–300)
• Transferrin saturation 54% (11%–46%).

2. Which of the following would be the best test to obtain next?

• Bone marrow examination
• Blood cultures
• Tuberculin skin test
• Liver biopsy
• Positron emission tomography and CT

Our patient has unexplained pancytopenia. While all the tests listed above might shed light on her condition, a bone marrow examination would be the best test to obtain next.

Urine histoplasma antigen studies are positive at greater than 39 ng/mL (normal 0, low positive < 0.6–3.9, moderate positive 4.0–19.9, high positive 20–39 ng/mL). A culture of the marrow subsequently grows this organism.

3. Which of the following tests would establish a definitive diagnosis in this patient?

• Methenamine silver stain of the marrow
• Serum antibody testing
• Fungal culture
• Peripheral blood smear
• Carbolfuchsin stain of marrow
• Urine histoplasma antigen

A prompt diagnosis is critical in patients with acute pulmonary histoplasmosis or progressive disseminated histoplasmosis because early treatment may shorten the clinical course and length of treatment and, in cases of disseminated histoplasmosis, prevent death.^8–10

Histopathologic examination of the bone marrow gives the most rapid results, although biopsy to obtain the tissue is invasive. It can give a definitive diagnosis if it reveals the typical 2- to 4-μm yeast structures of H capsulatum. These are observed on an aspirate smear of the patient’s bone marrow biopsy (Figure 1) and can be confirmed by methenamine silver or periodic acid-Schiff staining of the tissue.

Antibody detection is less practical because the antibodies take 2 to 6 weeks after infection to form.¹¹ Also, it is less useful in cases of disseminated infection because many of these patients are immunosuppressed.

Fungal culture remains the gold standard diagnostic test for histoplasmosis. However, results may take up to 1 month and may be falsely negative in less severe cases.

Histoplasma antigen testing is of greater utility in patients with severe disease, including cases of disseminated histoplasmosis. Rates of antigen detection approach 90% in urine specimens from non-AIDS patients with disseminated infection.¹² The urine assay has a greater sensitivity and specificity than the serum assay. The rate of detection is lower (ie, around 82%) in patients with acute pulmonary histoplasmosis when both the serum and urine specimens are tested.¹³

The immunoassay for histoplasma antigen is particularly useful for monitoring the response to therapy. Antigen levels should be measured before treatment is started and at 2 weeks, 1 month, and then approximately every 3 months during therapy.¹⁴ If the treatment is effective, antigens should decline by at least 20% in the first month of treatment and by another 20% in each of the following 3-month intervals. Antigen testing should be done every 3 months until a negative antigen level is achieved. The antigen level should also be followed for at least 6 months after treatment has stopped.¹⁴

HISTOPLASMA IS INHALED

H capsulatum is the cause of one of the most common pulmonary and systemic mycotic infections in the world, with hundreds of thousands of new cases annually. In areas where the soil is contaminated by bird or bat guano, the fungus is inhaled, resulting in an asymptomatic or a self-limiting influenza-like syndrome in an immunocompetent individual.¹⁵

An antigen-specific CD4⁺ T lymphocytemediated immunity occurs. The immune response of the host is thought to be fungistatic rather than fungicidal, resulting in a persistent inactive infection capable of reactivation in the presence of a host-pathogen imbalance.¹⁶

Most infections are asymptomatic or self-limited. For every 2,000 acute infections there is one that results in severe and progressive dissemination, usually in an immunocompromised host.^17,18

TREATMENT OF HISTOPLASMOSIS

4. What is the appropriate initial choice of treatment for a severe case of disseminated histoplasmosis?

• Amphotericin B in a lipid complex formulation (Abelcet)
• Itraconazole (Sporanox)
• Fluconazole (Diflucan)
• Ketoconazole (Nizoral)

Untreated, acute disseminated histoplasmosis can progress over a period of 2 to 12 weeks, ultimately killing the patient.^17,19

The leading therapies include amphotericin B in a lipid formulation and azole drugs, in particular itraconazole. Fluconazole and ketoconazole are not first-line options in severe cases because they are less predictably effective, and ketoconazole has a higher rate of side effects.^20–23 The current recommendation is to treat severely ill hospitalized patients with one of the liposomal formulations or the lipid complex formulation of amphotericin B. Itraconazole is used for patients who have mild to moderate symptoms and as a step-down therapy in patients who improve after initial use of amphotericin B.

CASE CONCLUDED: THE PATIENT RECOVERS

At the time of the initial patient encounter, there was no history of or obvious cause of immunosuppression in this patient. She was found to be HIV-negative and was subsequently diagnosed with “profound immunosuppression of unknown etiology” resulting in a low CD4 count.

The patient receives trimethoprim-sulfamethoxazole (Bactrim, Septra) and azithromycin (Zithromax) for prophylaxis against Pneumocystis carinii pneumonia and Mycobacterium avium intracellulare infection. Two months after the hospitalization, she recalls being at a corn maze 1 month before becoming ill.

What is the diagnosis? Is a cardiology consult warranted?

AN ABERRANT CONDUCTION PATTERN

The finding seen in this electrocardiogram is known as the Ashman phenomenon, an aberrant conduction pattern seen in atrial dysrhythmias, mainly atrial fibrillation, atrial tachycardia, and atrial ectopy, when a relatively long cycle is followed by a relatively short cycle. The beat terminating the short cycle often has the morphology of right bundle branch block.

This pattern was first described by Gouaux and Ashman in 1947; however, the aberrant conduction of supraventricular impulses was first described by Lewis in 1910.^1,2

Ashman phenomenon and right bundle branch block

The three criteria for the diagnosis of right bundle branch block in adults are:

• A QRS duration of 120 msec or more
• An rsr', rsR', or rSR' in leads V₁ or V₂ (the R' or r' deflection is usually wider than the initial R wave)
• The duration of the S wave in I and V₆ is usually greater than that of the R wave or is greater than 40 msec.³

Variation in the heart rate (due to atrial fibrillation in this patient) affects the width of the QRS interval; the refractory period of a cycle is influenced by the RR interval of the previous cycle. Therefore, if after a long cycle with a consequent long refractory period, a shorter cycle follows, then the beat terminating the short cycle is likely to be aberrantly conducted because one of the bundle branches is still in the refractory period. Because the refractory period for the right bundle branch is longer than that of the left bundle branch, the right bundle branch block pattern is more common.4

In our patient’s tracing (Figure 1), the aberrantly conducted beat has the shortest coupling intervals of any of the conducted beats on the tracing. Although the RR interval preceding the short cycle is not the longest on this tracing, it is moderately long, and so the refractory period of the right bundle branch is moderately long.

The Ashman pattern vs ventricular premature beat

Atrial arrhythmias cause a variation in the refractory period of the bundle branches and the ventricular conduction system, and this explains why the Ashman phenomenon occurs more often in this setting. It is important to distinguish the aberrant conduction seen in the Ashman phenomenon, which electrophysiologically is restricted to the His-Purkinje system, from premature ventricular complexes and ventricular tachycardia.

The current criteria used to distinguish the Ashman phenomenon were described by Fisch^5,6:

• A relatively long cycle immediately preceding the cycle terminated by the aberrant QRS complex: a short-long-short interval is even more likely to initiate aberration. The aberration can be left or right bundle branch block, or both, even in the same patient.
• Right bundle branch block morphology, with normal orientation of the initial QRS vector. Concealed perpetuation of the aberration is possible, and so a series of wide QRS supraventricular beats is possible.
• Irregular coupling of aberrant QRS complexes.
• Lack of a fully compensatory pause.

In Figure 1, the second aberrantly conducted beat is not as aberrant as the first, even though it is even more premature than the first. This can be explained because the refractory period of the right bundle branch has now shortened.

Also, the mechanism of aberrancy of the second beat may be partly the result of concealed perpetuation, ie, incomplete penetration of the His bundle depolarizations in either direction with secondary abnormalities of antegrade or retrograde conduction. This pattern is not directly reflected on the surface electrocardiogram but can be detected on intracardiac electrophysiologic studies.⁷ In concealed perpetuation, instead of inducing tachycardia, the extra stimuli are followed by pauses that exceed the tachycardia cycle length.⁸

Treated by managing the atrial arrhythmia

There is no specific treatment for the aberrant cycles. Rather, treatment is directed at the atrial arrhythmia.⁹ Adequate control of the underlying process and the atrial tachyarrhythmia itself is important. In our patient, control of the exacerbation of chronic obstructive pulmonary disease and of the heart rate improved the ventricular response to atrial fibrillation.

What is the diagnosis? Is a cardiology consult warranted?

AN ABERRANT CONDUCTION PATTERN

The finding seen in this electrocardiogram is known as the Ashman phenomenon, an aberrant conduction pattern seen in atrial dysrhythmias, mainly atrial fibrillation, atrial tachycardia, and atrial ectopy, when a relatively long cycle is followed by a relatively short cycle. The beat terminating the short cycle often has the morphology of right bundle branch block.

This pattern was first described by Gouaux and Ashman in 1947; however, the aberrant conduction of supraventricular impulses was first described by Lewis in 1910.^1,2

Ashman phenomenon and right bundle branch block

The three criteria for the diagnosis of right bundle branch block in adults are:

• A QRS duration of 120 msec or more
• An rsr', rsR', or rSR' in leads V₁ or V₂ (the R' or r' deflection is usually wider than the initial R wave)
• The duration of the S wave in I and V₆ is usually greater than that of the R wave or is greater than 40 msec.³

Variation in the heart rate (due to atrial fibrillation in this patient) affects the width of the QRS interval; the refractory period of a cycle is influenced by the RR interval of the previous cycle. Therefore, if after a long cycle with a consequent long refractory period, a shorter cycle follows, then the beat terminating the short cycle is likely to be aberrantly conducted because one of the bundle branches is still in the refractory period. Because the refractory period for the right bundle branch is longer than that of the left bundle branch, the right bundle branch block pattern is more common.4

In our patient’s tracing (Figure 1), the aberrantly conducted beat has the shortest coupling intervals of any of the conducted beats on the tracing. Although the RR interval preceding the short cycle is not the longest on this tracing, it is moderately long, and so the refractory period of the right bundle branch is moderately long.

The Ashman pattern vs ventricular premature beat

Atrial arrhythmias cause a variation in the refractory period of the bundle branches and the ventricular conduction system, and this explains why the Ashman phenomenon occurs more often in this setting. It is important to distinguish the aberrant conduction seen in the Ashman phenomenon, which electrophysiologically is restricted to the His-Purkinje system, from premature ventricular complexes and ventricular tachycardia.

The current criteria used to distinguish the Ashman phenomenon were described by Fisch^5,6:

• A relatively long cycle immediately preceding the cycle terminated by the aberrant QRS complex: a short-long-short interval is even more likely to initiate aberration. The aberration can be left or right bundle branch block, or both, even in the same patient.
• Right bundle branch block morphology, with normal orientation of the initial QRS vector. Concealed perpetuation of the aberration is possible, and so a series of wide QRS supraventricular beats is possible.
• Irregular coupling of aberrant QRS complexes.
• Lack of a fully compensatory pause.

In Figure 1, the second aberrantly conducted beat is not as aberrant as the first, even though it is even more premature than the first. This can be explained because the refractory period of the right bundle branch has now shortened.

Also, the mechanism of aberrancy of the second beat may be partly the result of concealed perpetuation, ie, incomplete penetration of the His bundle depolarizations in either direction with secondary abnormalities of antegrade or retrograde conduction. This pattern is not directly reflected on the surface electrocardiogram but can be detected on intracardiac electrophysiologic studies.⁷ In concealed perpetuation, instead of inducing tachycardia, the extra stimuli are followed by pauses that exceed the tachycardia cycle length.⁸

Treated by managing the atrial arrhythmia

There is no specific treatment for the aberrant cycles. Rather, treatment is directed at the atrial arrhythmia.⁹ Adequate control of the underlying process and the atrial tachyarrhythmia itself is important. In our patient, control of the exacerbation of chronic obstructive pulmonary disease and of the heart rate improved the ventricular response to atrial fibrillation.

What is the diagnosis? Is a cardiology consult warranted?

AN ABERRANT CONDUCTION PATTERN

The finding seen in this electrocardiogram is known as the Ashman phenomenon, an aberrant conduction pattern seen in atrial dysrhythmias, mainly atrial fibrillation, atrial tachycardia, and atrial ectopy, when a relatively long cycle is followed by a relatively short cycle. The beat terminating the short cycle often has the morphology of right bundle branch block.

This pattern was first described by Gouaux and Ashman in 1947; however, the aberrant conduction of supraventricular impulses was first described by Lewis in 1910.^1,2

Ashman phenomenon and right bundle branch block

The three criteria for the diagnosis of right bundle branch block in adults are:

• A QRS duration of 120 msec or more
• An rsr', rsR', or rSR' in leads V₁ or V₂ (the R' or r' deflection is usually wider than the initial R wave)
• The duration of the S wave in I and V₆ is usually greater than that of the R wave or is greater than 40 msec.³

Variation in the heart rate (due to atrial fibrillation in this patient) affects the width of the QRS interval; the refractory period of a cycle is influenced by the RR interval of the previous cycle. Therefore, if after a long cycle with a consequent long refractory period, a shorter cycle follows, then the beat terminating the short cycle is likely to be aberrantly conducted because one of the bundle branches is still in the refractory period. Because the refractory period for the right bundle branch is longer than that of the left bundle branch, the right bundle branch block pattern is more common.4

In our patient’s tracing (Figure 1), the aberrantly conducted beat has the shortest coupling intervals of any of the conducted beats on the tracing. Although the RR interval preceding the short cycle is not the longest on this tracing, it is moderately long, and so the refractory period of the right bundle branch is moderately long.

The Ashman pattern vs ventricular premature beat

Atrial arrhythmias cause a variation in the refractory period of the bundle branches and the ventricular conduction system, and this explains why the Ashman phenomenon occurs more often in this setting. It is important to distinguish the aberrant conduction seen in the Ashman phenomenon, which electrophysiologically is restricted to the His-Purkinje system, from premature ventricular complexes and ventricular tachycardia.

The current criteria used to distinguish the Ashman phenomenon were described by Fisch^5,6:

• A relatively long cycle immediately preceding the cycle terminated by the aberrant QRS complex: a short-long-short interval is even more likely to initiate aberration. The aberration can be left or right bundle branch block, or both, even in the same patient.
• Right bundle branch block morphology, with normal orientation of the initial QRS vector. Concealed perpetuation of the aberration is possible, and so a series of wide QRS supraventricular beats is possible.
• Irregular coupling of aberrant QRS complexes.
• Lack of a fully compensatory pause.

In Figure 1, the second aberrantly conducted beat is not as aberrant as the first, even though it is even more premature than the first. This can be explained because the refractory period of the right bundle branch has now shortened.

Also, the mechanism of aberrancy of the second beat may be partly the result of concealed perpetuation, ie, incomplete penetration of the His bundle depolarizations in either direction with secondary abnormalities of antegrade or retrograde conduction. This pattern is not directly reflected on the surface electrocardiogram but can be detected on intracardiac electrophysiologic studies.⁷ In concealed perpetuation, instead of inducing tachycardia, the extra stimuli are followed by pauses that exceed the tachycardia cycle length.⁸

Treated by managing the atrial arrhythmia

There is no specific treatment for the aberrant cycles. Rather, treatment is directed at the atrial arrhythmia.⁹ Adequate control of the underlying process and the atrial tachyarrhythmia itself is important. In our patient, control of the exacerbation of chronic obstructive pulmonary disease and of the heart rate improved the ventricular response to atrial fibrillation.

A 48-year-old man reports progressive exercise intolerance, shortness of breath, fatigue, and melena over the past month. He has a long history of Raynaud phenomenon, and 5 months ago he developed severe sclerodactyly in both hands, diagnosed as limited cutaneous systemic sclerosis (scleroderma).

He has no chest pain, swelling of the lower limbs, change in weight, cough, fever, chills, or sick contacts, and he has not traveled recently.

His symptoms began as fatigue and shortness of breath, which worsened until he began having episodes of abdominal pain with melena and dizzy spills, although he never passed out.

He is currently taking long-term low-dose prednisone and mycophenolate mofetil (Cell-Cept) for the systemic sclerosis, and omeprazole (Prilosec) for gastroesophageal reflux. His father had lupus, and his grandmother had colon cancer.

An outpatient workup for sclerosis-related lung and heart involvement is negative. The workup includes computed tomography of the chest, pulmonary function tests, and Doppler echocardiography.

He is afebrile, with a blood pressure of 105/60 mm Hg and a pulse of 98. His cardiopulmonary examination results are normal. He has mild epigastric tenderness without rebound or guarding. His hemoglobin concentration at the time of hospital admission is 7.8 g/dL, down from 14.5 g/dL recorded when limited cutaneous systemic sclerosis was diagnosed. Iron studies reveal iron deficiency.

The antral ectasia is treated with argon plasma coagulation during the endoscopic examination.

Afterward, the patient's hemoglobin stabilizes, and the melena resolves. He is discharged on an oral proton pump inhibitor, with instructions to follow up for another endoscopic session in 1 month.

GASTROINTESTINAL FEATURES OF SYSTEMIC SCLEROSIS

Sclerodermal disorders have diverse manifestations that always include characteristic cutaneous signs. While there are several well-recognized symptomatic conditions commonly associated with scleroderma, attention must also be paid to the less common causes of these symptoms. Scleroderma has gastrointestinal complications that can easily be missed and may not respond to immunomodulatory or proton pump inhibitor therapy: complications can include esophageal dysmotility, hypomotility, gastric paresis, reflux esophagitis, strictures, drug-related ulcer, malabsorption, bacterial overgrowth, and pseudo-obstruction.¹

This patient had an underrecognized cause of dyspnea in the setting of systemic sclerosis. Vascular symptoms of limited cutaneous systemic sclerosis are typically attributed to Raynaud phenomenon; gastrointestinal symptoms are typically attributed to esophageal dysmotility; and associated dyspnea is often considered to represent pulmonary or cardiac involvement of the sclerosis. However, gastric antral vascular ectasia should be considered in any patient with scleroderma and evidence of anemia.

The prevalence of gastric antral vascular ectasia in patients with systemic sclerosis is estimated to be about 6%.^2–4 It is a relatively rare cause of upper gastrointestinal blood loss that can be clinically silent until the patient develops severe iron deficiency anemia and symptoms of dyspnea, fatigue, or congestive heart failure.

Gastric antral vascular ectasia in scleroderma usually presents as iron deficiency anemia, and only presents overtly as hematemesis or melena 10% to 14% of the time.⁴ Because of the often occult nature of the bleeding, the condition may be clinically silent in the early phase. Symptoms of shortness of breath and fatigue may not develop until the anemia worsens rapidly or becomes severe. Anemia is present in almost all cases of gastric antral vascular ectasia (96% to 100%) and should be a strong clinical clue for early endoscopic evaluation in patients with scleroderma, especially if there is already suspicion of upper gastrointestinal bleeding.^2–5

The distinctive endoscopic streaky pattern of ectasia along the stomach antrum seen in gastric antral vascular ectasia is called “watermelon stomach”^4,5 because the striped pattern recalls the stripes of a watermelon. The endoscopic appearance can vary, however, from the watermelon pattern to a coalescence of angiodysplastic lesions termed “honeycomb stomach,” which can easily be mistaken for antral gastritis.^4,5 Therefore, biopsy often serves to confirm the diagnosis, with histologic features including dilated mucosal capillaries with focal fibrin thrombosis and fibromuscular hyperplasia of the lamina propria.

Gastric antral vascular ectasia often requires multiple transfusions of red blood cells, as well as repeated treatments with endoscopic argon plasma coagulation, whereby ionized argon gas is used to conduct an electric current that coagulates the surface of the mucosa to a few millimeters depth.^4–6

A knowledge of the association between scleroderma and gastric antral vascular ectasia can lead to earlier recognition and treatment and can avoid unnecessary testing and complications of severe anemia.

A 48-year-old man reports progressive exercise intolerance, shortness of breath, fatigue, and melena over the past month. He has a long history of Raynaud phenomenon, and 5 months ago he developed severe sclerodactyly in both hands, diagnosed as limited cutaneous systemic sclerosis (scleroderma).

He has no chest pain, swelling of the lower limbs, change in weight, cough, fever, chills, or sick contacts, and he has not traveled recently.

His symptoms began as fatigue and shortness of breath, which worsened until he began having episodes of abdominal pain with melena and dizzy spills, although he never passed out.

He is currently taking long-term low-dose prednisone and mycophenolate mofetil (Cell-Cept) for the systemic sclerosis, and omeprazole (Prilosec) for gastroesophageal reflux. His father had lupus, and his grandmother had colon cancer.

An outpatient workup for sclerosis-related lung and heart involvement is negative. The workup includes computed tomography of the chest, pulmonary function tests, and Doppler echocardiography.

He is afebrile, with a blood pressure of 105/60 mm Hg and a pulse of 98. His cardiopulmonary examination results are normal. He has mild epigastric tenderness without rebound or guarding. His hemoglobin concentration at the time of hospital admission is 7.8 g/dL, down from 14.5 g/dL recorded when limited cutaneous systemic sclerosis was diagnosed. Iron studies reveal iron deficiency.

The antral ectasia is treated with argon plasma coagulation during the endoscopic examination.

Afterward, the patient's hemoglobin stabilizes, and the melena resolves. He is discharged on an oral proton pump inhibitor, with instructions to follow up for another endoscopic session in 1 month.

GASTROINTESTINAL FEATURES OF SYSTEMIC SCLEROSIS

Sclerodermal disorders have diverse manifestations that always include characteristic cutaneous signs. While there are several well-recognized symptomatic conditions commonly associated with scleroderma, attention must also be paid to the less common causes of these symptoms. Scleroderma has gastrointestinal complications that can easily be missed and may not respond to immunomodulatory or proton pump inhibitor therapy: complications can include esophageal dysmotility, hypomotility, gastric paresis, reflux esophagitis, strictures, drug-related ulcer, malabsorption, bacterial overgrowth, and pseudo-obstruction.¹

This patient had an underrecognized cause of dyspnea in the setting of systemic sclerosis. Vascular symptoms of limited cutaneous systemic sclerosis are typically attributed to Raynaud phenomenon; gastrointestinal symptoms are typically attributed to esophageal dysmotility; and associated dyspnea is often considered to represent pulmonary or cardiac involvement of the sclerosis. However, gastric antral vascular ectasia should be considered in any patient with scleroderma and evidence of anemia.

The prevalence of gastric antral vascular ectasia in patients with systemic sclerosis is estimated to be about 6%.^2–4 It is a relatively rare cause of upper gastrointestinal blood loss that can be clinically silent until the patient develops severe iron deficiency anemia and symptoms of dyspnea, fatigue, or congestive heart failure.

Gastric antral vascular ectasia in scleroderma usually presents as iron deficiency anemia, and only presents overtly as hematemesis or melena 10% to 14% of the time.⁴ Because of the often occult nature of the bleeding, the condition may be clinically silent in the early phase. Symptoms of shortness of breath and fatigue may not develop until the anemia worsens rapidly or becomes severe. Anemia is present in almost all cases of gastric antral vascular ectasia (96% to 100%) and should be a strong clinical clue for early endoscopic evaluation in patients with scleroderma, especially if there is already suspicion of upper gastrointestinal bleeding.^2–5

The distinctive endoscopic streaky pattern of ectasia along the stomach antrum seen in gastric antral vascular ectasia is called “watermelon stomach”^4,5 because the striped pattern recalls the stripes of a watermelon. The endoscopic appearance can vary, however, from the watermelon pattern to a coalescence of angiodysplastic lesions termed “honeycomb stomach,” which can easily be mistaken for antral gastritis.^4,5 Therefore, biopsy often serves to confirm the diagnosis, with histologic features including dilated mucosal capillaries with focal fibrin thrombosis and fibromuscular hyperplasia of the lamina propria.

Gastric antral vascular ectasia often requires multiple transfusions of red blood cells, as well as repeated treatments with endoscopic argon plasma coagulation, whereby ionized argon gas is used to conduct an electric current that coagulates the surface of the mucosa to a few millimeters depth.^4–6

A knowledge of the association between scleroderma and gastric antral vascular ectasia can lead to earlier recognition and treatment and can avoid unnecessary testing and complications of severe anemia.

A 48-year-old man reports progressive exercise intolerance, shortness of breath, fatigue, and melena over the past month. He has a long history of Raynaud phenomenon, and 5 months ago he developed severe sclerodactyly in both hands, diagnosed as limited cutaneous systemic sclerosis (scleroderma).

He has no chest pain, swelling of the lower limbs, change in weight, cough, fever, chills, or sick contacts, and he has not traveled recently.

His symptoms began as fatigue and shortness of breath, which worsened until he began having episodes of abdominal pain with melena and dizzy spills, although he never passed out.

He is currently taking long-term low-dose prednisone and mycophenolate mofetil (Cell-Cept) for the systemic sclerosis, and omeprazole (Prilosec) for gastroesophageal reflux. His father had lupus, and his grandmother had colon cancer.

An outpatient workup for sclerosis-related lung and heart involvement is negative. The workup includes computed tomography of the chest, pulmonary function tests, and Doppler echocardiography.

He is afebrile, with a blood pressure of 105/60 mm Hg and a pulse of 98. His cardiopulmonary examination results are normal. He has mild epigastric tenderness without rebound or guarding. His hemoglobin concentration at the time of hospital admission is 7.8 g/dL, down from 14.5 g/dL recorded when limited cutaneous systemic sclerosis was diagnosed. Iron studies reveal iron deficiency.

The antral ectasia is treated with argon plasma coagulation during the endoscopic examination.

Afterward, the patient's hemoglobin stabilizes, and the melena resolves. He is discharged on an oral proton pump inhibitor, with instructions to follow up for another endoscopic session in 1 month.

GASTROINTESTINAL FEATURES OF SYSTEMIC SCLEROSIS

Sclerodermal disorders have diverse manifestations that always include characteristic cutaneous signs. While there are several well-recognized symptomatic conditions commonly associated with scleroderma, attention must also be paid to the less common causes of these symptoms. Scleroderma has gastrointestinal complications that can easily be missed and may not respond to immunomodulatory or proton pump inhibitor therapy: complications can include esophageal dysmotility, hypomotility, gastric paresis, reflux esophagitis, strictures, drug-related ulcer, malabsorption, bacterial overgrowth, and pseudo-obstruction.¹

This patient had an underrecognized cause of dyspnea in the setting of systemic sclerosis. Vascular symptoms of limited cutaneous systemic sclerosis are typically attributed to Raynaud phenomenon; gastrointestinal symptoms are typically attributed to esophageal dysmotility; and associated dyspnea is often considered to represent pulmonary or cardiac involvement of the sclerosis. However, gastric antral vascular ectasia should be considered in any patient with scleroderma and evidence of anemia.

The prevalence of gastric antral vascular ectasia in patients with systemic sclerosis is estimated to be about 6%.^2–4 It is a relatively rare cause of upper gastrointestinal blood loss that can be clinically silent until the patient develops severe iron deficiency anemia and symptoms of dyspnea, fatigue, or congestive heart failure.

Gastric antral vascular ectasia in scleroderma usually presents as iron deficiency anemia, and only presents overtly as hematemesis or melena 10% to 14% of the time.⁴ Because of the often occult nature of the bleeding, the condition may be clinically silent in the early phase. Symptoms of shortness of breath and fatigue may not develop until the anemia worsens rapidly or becomes severe. Anemia is present in almost all cases of gastric antral vascular ectasia (96% to 100%) and should be a strong clinical clue for early endoscopic evaluation in patients with scleroderma, especially if there is already suspicion of upper gastrointestinal bleeding.^2–5

The distinctive endoscopic streaky pattern of ectasia along the stomach antrum seen in gastric antral vascular ectasia is called “watermelon stomach”^4,5 because the striped pattern recalls the stripes of a watermelon. The endoscopic appearance can vary, however, from the watermelon pattern to a coalescence of angiodysplastic lesions termed “honeycomb stomach,” which can easily be mistaken for antral gastritis.^4,5 Therefore, biopsy often serves to confirm the diagnosis, with histologic features including dilated mucosal capillaries with focal fibrin thrombosis and fibromuscular hyperplasia of the lamina propria.

Gastric antral vascular ectasia often requires multiple transfusions of red blood cells, as well as repeated treatments with endoscopic argon plasma coagulation, whereby ionized argon gas is used to conduct an electric current that coagulates the surface of the mucosa to a few millimeters depth.^4–6

A knowledge of the association between scleroderma and gastric antral vascular ectasia can lead to earlier recognition and treatment and can avoid unnecessary testing and complications of severe anemia.

A 25-year-old man presented to his primary care physician with generalized malaise. His symptoms started around 2 months earlier with progressive fatigue, nausea, decreased appetite, and weight loss (15 lb in 2 months). He denied having fever, chills, night sweats, abdominal pain, diarrhea, melena, or hematochezia.

His medical history was remarkable only for depression, well controlled with sertraline (Zoloft), which he started taking 3 years ago. He was not taking any other prescribed, over-the-counter, or herbal medications.

He had no family history of cancer or liver disease. He did not smoke and rarely drank alcohol. He had never used recreational drugs. He was sexually active with one female partner, used condoms for protection, and had never been diagnosed with a sexually transmitted disease. He had not traveled recently and had not been exposed to any pet.

The patient’s laboratory values on admission are shown in Table 1. Of note, his serum alkaline phosphatase level was 1,307 U/L (reference range 40–150 U/L).

LIVER TESTS CAN NARROW THE DIAGNOSIS

The most commonly used laboratory tests of the liver can be classified into those that measure either:

• Liver synthetic function (eg, the serum albumin and bilirubin concentrations and the prothrombin time) or
• Liver damage, as reflected by the serum concentrations of the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and gamma-glutamyltransferase (GGT).^1,2

ALT and AST are normally concentrated in the hepatocytes and thus, when present in the serum in elevated concentrations, are markers of liver cell injury. The serum levels of these enzymes start to increase within a few hours of liver cell injury as they leak out of the cells via the damaged cell membrane. AST is less liver-specific than ALT, since AST levels can be elevated not only in liver injury but also in muscle, cardiac, and red blood cell injury.^3,4

Alkaline phosphatase is actually a heterogeneous group of enzymes found mainly in liver and bone cells. Hepatic alkaline phosphatase is concentrated near the biliary canalicular membrane of the hepatocyte. Accordingly, increased levels of hepatic alkaline phosphatase are mainly seen in liver diseases that predominantly affect the biliary system.³

GGT is also concentrated in hepatic biliary epithelial cells, and thus GGT elevation is another marker of hepatobiliary disease. In fact, measuring the GGT level can help to determine whether an isolated elevation of alkaline phosphatase is due to liver injury.^2,3

Accordingly, liver diseases can be classified into two broad categories:

• Hepatocellular injury, in which the primary injury occurs to the hepatocytes
• Cholestatic injury, in which the primary injury is to the bile ducts.

In the former, elevated levels of ALT and AST predominate, while in the latter, elevated alkaline phosphatase is the main finding.³

WHAT TEST NEXT FOR OUR PATIENT?

1. What is the next most appropriate diagnostic step for our patient?

• Liver biopsy
• Ultrasonography of the liver
• Computed tomography (CT) of the liver
• Observation

Our patient has an elevated GGT level, which suggests that his elevated alkaline phosphatase is of hepatic rather than bony origin. Moreover, a serum alkaline phosphatase level that is elevated out of proportion to the aminotransferase levels reflects cholestatic liver injury.

CASE CONTINUED: ULTRASONOGRAPHY IS MOSTLY NORMAL

Ultrasonography of the right upper quadrant revealed that the liver had normal echogenicity and was mildly enlarged. There was no focal hepatic lesion. The gallbladder appeared normal, with no stones or sludge. No dilated intrahepatic or extrahepatic biliary ducts were seen. The common bile duct measured 4 mm. A small amount of ascites not amenable to paracentesis was present.

Thus, in the absence of biliary dilation on ultrasonography, we are dealing with an intrahepatic cholestatic process.

CAUSES OF CHOLESTATIC LIVER DISEASE

Viral hepatitis

Viral hepatitis most often produces a hepatocellular pattern of injury (ie, AST and ALT elevations predominate). However, in rare cases it can cause a cholestatic pattern of injury.

Our patient subsequently had serologic tests for viral hepatitis, including hepatitis A, B, and C, and the results were negative.

Autoimmune liver disease

The three most common forms of autoimmune liver disease are autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis.

Autoimmune hepatitis is characterized by high serum ALT and AST levels, whereas primary biliary cirrhosis and primary sclerosing cholangitis are associated with predominant elevations of alkaline phosphatase, since they are cholestatic disorders.

Our patient’s alkaline phosphatase level was much higher than his ALT and AST levels, making the latter two diseases more likely.

Primary biliary cirrhosis (and autoimmune hepatitis) are associated with autoantibodies in the serum, such as antinuclear antibody, smooth muscle antibody, and antimitochondrial antibody.

Our patient subsequently was tested for these antibodies, and the results were negative.

Primary sclerosing cholangitis usually affects the extrahepatic biliary system. Thus, if it is present, abnormalities should be seen on imaging.

As mentioned previously, no dilated intrahepatic or extrahepatic biliary ducts were seen on ultrasonography in our patient. Moreover, primary sclerosing cholangitis is associated with inflammatory bowel disease, particularly ulcerative colitis, which our patient did not have.

Drug-induced liver injury

Drug-induced liver injury is a common cause of cholestatic liver disease. However, our patient was not taking any prescribed, over-the-counter, or herbal medications. Additionally, he denied heavy alcohol use.

Infiltrative disorders

Infiltrative disorders such as amyloidosis, sarcoidosis, or lymphoma should be considered in the differential diagnosis of cholestatic liver disease. A clue to a possible infiltrative process is a markedly elevated level of alkaline phosphatase with a mildly increased serum bilirubin concentration, both of which our patient had.

AFTER ULTRASONOGRAPHY, WHAT IS THE NEXT STEP?

2. Which of the following is the next most appropriate diagnostic test for our patient?

• Endoscopic retrograde cholangiopancreatography (ERCP)
• Magnetic resonance cholangiopancreatography (MRCP)
• Liver biopsy
• CT of the abdomen

Figure 1 shows a proposed algorithm for evaluating increased alkaline phosphatase levels.

If there is no biliary duct dilation on ultrasonography, then abnormal levels of alkaline phosphatase most likely represent an intrahepatic pattern of cholestatic liver injury. Therefore, additional imaging with CT or magnetic resonance imaging is of limited diagnostic value. ERCP is used today for therapy rather than diagnosis, so its use is limited to patients known to have dilated biliary ducts on imaging. Liver biopsy, however, can provide useful findings.

Case continued: He undergoes biopsy

Our patient underwent transjugular liver biopsy. During the procedure, transjugular venography showed stenosis in the right, middle, and left hepatic veins and the hepatic portion of the inferior vena cava, consistent with Budd-Chiari syndrome.

The liver biopsy specimen was positive for extensive deposition of slight eosinophilic and amorphous material in a sinusoidal pattern in the liver parenchyma, as well as in the portal tracts, with markedly atrophic hepatocytes. Congo red birefringence confirmed the diagnosis of amyloidosis. The immunohistochemical phenotype was positive for kappa light chains, which is diagnostic for primary-type amyloidosis, also called amyloidosis of light chain composition, or AL.

Bone marrow aspiration and bone marrow biopsy were performed and showed 22% plasma cells, well above the normal range (0–2%), consistent with the diagnosis of multiple myeloma.

BUDD-CHIARI SYNDROME: A CHALLENGING DIAGNOSIS

Budd-Chiari syndrome is a rare condition characterized by obstruction of venous outflow from the liver at a site that may vary from the small hepatic veins up to the inferior vena cava or even the right atrium.^5,6 Obstruction of hepatic venous outflow leads to sinusoidal congestion and hypoxic damage of the hepatocytes.⁷ Hypoxia and necrosis of the hepatocytes result in the release of free radicals. Cirrhosis can eventually occur secondary to ischemic necrosis of hepatocytes and hepatic fibrosis.⁸

The estimated incidence of this syndrome is 1 in 2.5 million persons per year.⁷ It is more prevalent in women and young adults.⁸

Heterogeneous in its causes and manifestations

Budd-Chiari syndrome is also heterogeneous in its manifestations, which depend on the extent of the occlusion, on the acuteness of the obstruction, and on whether venous collateral circulation has developed to decompress the liver sinusoids.^9,12,13 Therefore, on the basis of its clinical manifestations, it can be classified as fulminant, acute, subacute, or chronic.^12–16

The fulminant form presents with hepatic encephalopathy within 8 weeks after the development of jaundice. The subacute form, which is the most common, has a more insidious onset in which hepatic sinusoids are decompressed by portal and hepatic venous collateral circulation. The patient usually presents with abdominal pain, ascites, hepatomegaly, nausea, vomiting, and mild jaundice. Finally the chronic form presents as complications of cirrhosis.^12–16

Imaging plays an important role in diagnosing Budd-Chiari syndrome

Imaging plays an important role in detecting and classifying Budd-Chiari syndrome.

Duplex ultrasonography is useful for detecting this syndrome and has a sensitivity and specificity of 85%.⁹

CT and magnetic resonance imaging can also help in the diagnosis by showing thrombosis, obstruction, or occlusion in the hepatic vein or the inferior vena cava.⁵

Venography is the gold standard for diagnosis. However, it should be performed only if noninvasive tests are negative or nondiagnostic and there is a high clinical suspicion of this disease.¹⁷ Budd-Chiari syndrome has a characteristic pattern on venography known as “spider web,” which is due to the formation of venous collaterals to bypass the occluded hepatic veins.⁹

Liver biopsy is not necessarily required to confirm the diagnosis of Budd-Chiari syndrome, but it can help in diagnosing the acute or subacute forms and also in ruling out other causes. Histologic findings can include centrizonal congestion, loss of hepatocytes, hemorrhage, and fibrosis.^18,19 Regenerative nodules are found in about 25% of patients.¹⁹

TREATING BUDD-CHIARI SYNDROME

The primary goal of treatment is to prevent further extension of the venous thrombosis in the hepatic veins, in their collaterals, and in the intrahepatic and extrahepatic portal venous system. Resolution of hepatic congestion improves liver perfusion and preserves function of the hepatocytes.

Anticoagulation is recommended in the early stages. Heparin therapy should be initiated and subsequently switched to warfarin with the goal of achieving an international normalized ratio of the prothrombin time of 2.0 to 2.5.^8,9,19

Thrombolysis is effective in the acute form.^20,21 Recanalization, including percutaneous or transhepatic angioplasty of localized segments of the narrowed hepatic veins or inferior vena cava, has long-term patency rates of 80% to 90%.²²

If thrombolytic therapy and angioplasty are unsuccessful, a transjugular intrahepatic portosystemic shunt or a surgical procedure (side-to-side portocaval shunt, central splenorenal shunt, or mesocaval shunt) should be considered.⁹

Liver transplantation is another treatment option in those with fulminant Budd-Chiari syndrome or advanced liver cirrhosis.⁸

PROGNOSIS HAS IMPROVED

The prognosis of Budd-Chiari syndrome has improved, thanks to both earlier diagnosis and new treatments. The 1-year survival rate, which was about 60% before 1985, has increased to more than 80% in recent cohort studies.¹⁹

Studies have shown that the Child-Pugh score, which is based on a combination of serum albumin, bilirubin, prothrombin time, encephalopathy, and ascites, can be considered as an independent prognostic factor. A lower Child-Pugh score and a younger age are associated with a good prognosis.^19,23,24 (The Child-Pugh score cannot be applied to our patient because he does not have cirrhosis.)

What happened to our patient?

Our patient was started on anticoagulation for his Budd-Chiari syndrome and on bortezomib (Velcade) and dexamethasone for his multiple myeloma. He achieved remarkable improvement in his liver function tests. Follow-up duplex ultrasonography 1 month after discharge revealed that the stenosis in the hepatic veins had resolved. He is following up with the oncology clinic for management of his multiple myeloma.

A 25-year-old man presented to his primary care physician with generalized malaise. His symptoms started around 2 months earlier with progressive fatigue, nausea, decreased appetite, and weight loss (15 lb in 2 months). He denied having fever, chills, night sweats, abdominal pain, diarrhea, melena, or hematochezia.

His medical history was remarkable only for depression, well controlled with sertraline (Zoloft), which he started taking 3 years ago. He was not taking any other prescribed, over-the-counter, or herbal medications.

He had no family history of cancer or liver disease. He did not smoke and rarely drank alcohol. He had never used recreational drugs. He was sexually active with one female partner, used condoms for protection, and had never been diagnosed with a sexually transmitted disease. He had not traveled recently and had not been exposed to any pet.

The patient’s laboratory values on admission are shown in Table 1. Of note, his serum alkaline phosphatase level was 1,307 U/L (reference range 40–150 U/L).

LIVER TESTS CAN NARROW THE DIAGNOSIS

The most commonly used laboratory tests of the liver can be classified into those that measure either:

• Liver synthetic function (eg, the serum albumin and bilirubin concentrations and the prothrombin time) or
• Liver damage, as reflected by the serum concentrations of the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and gamma-glutamyltransferase (GGT).^1,2

ALT and AST are normally concentrated in the hepatocytes and thus, when present in the serum in elevated concentrations, are markers of liver cell injury. The serum levels of these enzymes start to increase within a few hours of liver cell injury as they leak out of the cells via the damaged cell membrane. AST is less liver-specific than ALT, since AST levels can be elevated not only in liver injury but also in muscle, cardiac, and red blood cell injury.^3,4

Alkaline phosphatase is actually a heterogeneous group of enzymes found mainly in liver and bone cells. Hepatic alkaline phosphatase is concentrated near the biliary canalicular membrane of the hepatocyte. Accordingly, increased levels of hepatic alkaline phosphatase are mainly seen in liver diseases that predominantly affect the biliary system.³

GGT is also concentrated in hepatic biliary epithelial cells, and thus GGT elevation is another marker of hepatobiliary disease. In fact, measuring the GGT level can help to determine whether an isolated elevation of alkaline phosphatase is due to liver injury.^2,3

Accordingly, liver diseases can be classified into two broad categories:

• Hepatocellular injury, in which the primary injury occurs to the hepatocytes
• Cholestatic injury, in which the primary injury is to the bile ducts.

In the former, elevated levels of ALT and AST predominate, while in the latter, elevated alkaline phosphatase is the main finding.³

WHAT TEST NEXT FOR OUR PATIENT?

1. What is the next most appropriate diagnostic step for our patient?

• Liver biopsy
• Ultrasonography of the liver
• Computed tomography (CT) of the liver
• Observation

Our patient has an elevated GGT level, which suggests that his elevated alkaline phosphatase is of hepatic rather than bony origin. Moreover, a serum alkaline phosphatase level that is elevated out of proportion to the aminotransferase levels reflects cholestatic liver injury.

CASE CONTINUED: ULTRASONOGRAPHY IS MOSTLY NORMAL

Ultrasonography of the right upper quadrant revealed that the liver had normal echogenicity and was mildly enlarged. There was no focal hepatic lesion. The gallbladder appeared normal, with no stones or sludge. No dilated intrahepatic or extrahepatic biliary ducts were seen. The common bile duct measured 4 mm. A small amount of ascites not amenable to paracentesis was present.

Thus, in the absence of biliary dilation on ultrasonography, we are dealing with an intrahepatic cholestatic process.

CAUSES OF CHOLESTATIC LIVER DISEASE

Viral hepatitis

Viral hepatitis most often produces a hepatocellular pattern of injury (ie, AST and ALT elevations predominate). However, in rare cases it can cause a cholestatic pattern of injury.

Our patient subsequently had serologic tests for viral hepatitis, including hepatitis A, B, and C, and the results were negative.

Autoimmune liver disease

The three most common forms of autoimmune liver disease are autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis.

Autoimmune hepatitis is characterized by high serum ALT and AST levels, whereas primary biliary cirrhosis and primary sclerosing cholangitis are associated with predominant elevations of alkaline phosphatase, since they are cholestatic disorders.

Our patient’s alkaline phosphatase level was much higher than his ALT and AST levels, making the latter two diseases more likely.

Primary biliary cirrhosis (and autoimmune hepatitis) are associated with autoantibodies in the serum, such as antinuclear antibody, smooth muscle antibody, and antimitochondrial antibody.

Our patient subsequently was tested for these antibodies, and the results were negative.

Primary sclerosing cholangitis usually affects the extrahepatic biliary system. Thus, if it is present, abnormalities should be seen on imaging.

As mentioned previously, no dilated intrahepatic or extrahepatic biliary ducts were seen on ultrasonography in our patient. Moreover, primary sclerosing cholangitis is associated with inflammatory bowel disease, particularly ulcerative colitis, which our patient did not have.

Drug-induced liver injury

Drug-induced liver injury is a common cause of cholestatic liver disease. However, our patient was not taking any prescribed, over-the-counter, or herbal medications. Additionally, he denied heavy alcohol use.

Infiltrative disorders

Infiltrative disorders such as amyloidosis, sarcoidosis, or lymphoma should be considered in the differential diagnosis of cholestatic liver disease. A clue to a possible infiltrative process is a markedly elevated level of alkaline phosphatase with a mildly increased serum bilirubin concentration, both of which our patient had.

AFTER ULTRASONOGRAPHY, WHAT IS THE NEXT STEP?

2. Which of the following is the next most appropriate diagnostic test for our patient?

• Endoscopic retrograde cholangiopancreatography (ERCP)
• Magnetic resonance cholangiopancreatography (MRCP)
• Liver biopsy
• CT of the abdomen

Figure 1 shows a proposed algorithm for evaluating increased alkaline phosphatase levels.

If there is no biliary duct dilation on ultrasonography, then abnormal levels of alkaline phosphatase most likely represent an intrahepatic pattern of cholestatic liver injury. Therefore, additional imaging with CT or magnetic resonance imaging is of limited diagnostic value. ERCP is used today for therapy rather than diagnosis, so its use is limited to patients known to have dilated biliary ducts on imaging. Liver biopsy, however, can provide useful findings.

Case continued: He undergoes biopsy

Our patient underwent transjugular liver biopsy. During the procedure, transjugular venography showed stenosis in the right, middle, and left hepatic veins and the hepatic portion of the inferior vena cava, consistent with Budd-Chiari syndrome.

The liver biopsy specimen was positive for extensive deposition of slight eosinophilic and amorphous material in a sinusoidal pattern in the liver parenchyma, as well as in the portal tracts, with markedly atrophic hepatocytes. Congo red birefringence confirmed the diagnosis of amyloidosis. The immunohistochemical phenotype was positive for kappa light chains, which is diagnostic for primary-type amyloidosis, also called amyloidosis of light chain composition, or AL.

Bone marrow aspiration and bone marrow biopsy were performed and showed 22% plasma cells, well above the normal range (0–2%), consistent with the diagnosis of multiple myeloma.

BUDD-CHIARI SYNDROME: A CHALLENGING DIAGNOSIS

Budd-Chiari syndrome is a rare condition characterized by obstruction of venous outflow from the liver at a site that may vary from the small hepatic veins up to the inferior vena cava or even the right atrium.^5,6 Obstruction of hepatic venous outflow leads to sinusoidal congestion and hypoxic damage of the hepatocytes.⁷ Hypoxia and necrosis of the hepatocytes result in the release of free radicals. Cirrhosis can eventually occur secondary to ischemic necrosis of hepatocytes and hepatic fibrosis.⁸

The estimated incidence of this syndrome is 1 in 2.5 million persons per year.⁷ It is more prevalent in women and young adults.⁸

Heterogeneous in its causes and manifestations

Budd-Chiari syndrome is also heterogeneous in its manifestations, which depend on the extent of the occlusion, on the acuteness of the obstruction, and on whether venous collateral circulation has developed to decompress the liver sinusoids.^9,12,13 Therefore, on the basis of its clinical manifestations, it can be classified as fulminant, acute, subacute, or chronic.^12–16

The fulminant form presents with hepatic encephalopathy within 8 weeks after the development of jaundice. The subacute form, which is the most common, has a more insidious onset in which hepatic sinusoids are decompressed by portal and hepatic venous collateral circulation. The patient usually presents with abdominal pain, ascites, hepatomegaly, nausea, vomiting, and mild jaundice. Finally the chronic form presents as complications of cirrhosis.^12–16

Imaging plays an important role in diagnosing Budd-Chiari syndrome

Imaging plays an important role in detecting and classifying Budd-Chiari syndrome.

Duplex ultrasonography is useful for detecting this syndrome and has a sensitivity and specificity of 85%.⁹

CT and magnetic resonance imaging can also help in the diagnosis by showing thrombosis, obstruction, or occlusion in the hepatic vein or the inferior vena cava.⁵

Venography is the gold standard for diagnosis. However, it should be performed only if noninvasive tests are negative or nondiagnostic and there is a high clinical suspicion of this disease.¹⁷ Budd-Chiari syndrome has a characteristic pattern on venography known as “spider web,” which is due to the formation of venous collaterals to bypass the occluded hepatic veins.⁹

Liver biopsy is not necessarily required to confirm the diagnosis of Budd-Chiari syndrome, but it can help in diagnosing the acute or subacute forms and also in ruling out other causes. Histologic findings can include centrizonal congestion, loss of hepatocytes, hemorrhage, and fibrosis.^18,19 Regenerative nodules are found in about 25% of patients.¹⁹

TREATING BUDD-CHIARI SYNDROME

The primary goal of treatment is to prevent further extension of the venous thrombosis in the hepatic veins, in their collaterals, and in the intrahepatic and extrahepatic portal venous system. Resolution of hepatic congestion improves liver perfusion and preserves function of the hepatocytes.

Anticoagulation is recommended in the early stages. Heparin therapy should be initiated and subsequently switched to warfarin with the goal of achieving an international normalized ratio of the prothrombin time of 2.0 to 2.5.^8,9,19

Thrombolysis is effective in the acute form.^20,21 Recanalization, including percutaneous or transhepatic angioplasty of localized segments of the narrowed hepatic veins or inferior vena cava, has long-term patency rates of 80% to 90%.²²

If thrombolytic therapy and angioplasty are unsuccessful, a transjugular intrahepatic portosystemic shunt or a surgical procedure (side-to-side portocaval shunt, central splenorenal shunt, or mesocaval shunt) should be considered.⁹

Liver transplantation is another treatment option in those with fulminant Budd-Chiari syndrome or advanced liver cirrhosis.⁸

PROGNOSIS HAS IMPROVED

The prognosis of Budd-Chiari syndrome has improved, thanks to both earlier diagnosis and new treatments. The 1-year survival rate, which was about 60% before 1985, has increased to more than 80% in recent cohort studies.¹⁹

Studies have shown that the Child-Pugh score, which is based on a combination of serum albumin, bilirubin, prothrombin time, encephalopathy, and ascites, can be considered as an independent prognostic factor. A lower Child-Pugh score and a younger age are associated with a good prognosis.^19,23,24 (The Child-Pugh score cannot be applied to our patient because he does not have cirrhosis.)

What happened to our patient?

Our patient was started on anticoagulation for his Budd-Chiari syndrome and on bortezomib (Velcade) and dexamethasone for his multiple myeloma. He achieved remarkable improvement in his liver function tests. Follow-up duplex ultrasonography 1 month after discharge revealed that the stenosis in the hepatic veins had resolved. He is following up with the oncology clinic for management of his multiple myeloma.

A 25-year-old man presented to his primary care physician with generalized malaise. His symptoms started around 2 months earlier with progressive fatigue, nausea, decreased appetite, and weight loss (15 lb in 2 months). He denied having fever, chills, night sweats, abdominal pain, diarrhea, melena, or hematochezia.

His medical history was remarkable only for depression, well controlled with sertraline (Zoloft), which he started taking 3 years ago. He was not taking any other prescribed, over-the-counter, or herbal medications.

He had no family history of cancer or liver disease. He did not smoke and rarely drank alcohol. He had never used recreational drugs. He was sexually active with one female partner, used condoms for protection, and had never been diagnosed with a sexually transmitted disease. He had not traveled recently and had not been exposed to any pet.

The patient’s laboratory values on admission are shown in Table 1. Of note, his serum alkaline phosphatase level was 1,307 U/L (reference range 40–150 U/L).

LIVER TESTS CAN NARROW THE DIAGNOSIS

The most commonly used laboratory tests of the liver can be classified into those that measure either:

• Liver synthetic function (eg, the serum albumin and bilirubin concentrations and the prothrombin time) or
• Liver damage, as reflected by the serum concentrations of the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and gamma-glutamyltransferase (GGT).^1,2

ALT and AST are normally concentrated in the hepatocytes and thus, when present in the serum in elevated concentrations, are markers of liver cell injury. The serum levels of these enzymes start to increase within a few hours of liver cell injury as they leak out of the cells via the damaged cell membrane. AST is less liver-specific than ALT, since AST levels can be elevated not only in liver injury but also in muscle, cardiac, and red blood cell injury.^3,4

Alkaline phosphatase is actually a heterogeneous group of enzymes found mainly in liver and bone cells. Hepatic alkaline phosphatase is concentrated near the biliary canalicular membrane of the hepatocyte. Accordingly, increased levels of hepatic alkaline phosphatase are mainly seen in liver diseases that predominantly affect the biliary system.³

GGT is also concentrated in hepatic biliary epithelial cells, and thus GGT elevation is another marker of hepatobiliary disease. In fact, measuring the GGT level can help to determine whether an isolated elevation of alkaline phosphatase is due to liver injury.^2,3

Accordingly, liver diseases can be classified into two broad categories:

• Hepatocellular injury, in which the primary injury occurs to the hepatocytes
• Cholestatic injury, in which the primary injury is to the bile ducts.

In the former, elevated levels of ALT and AST predominate, while in the latter, elevated alkaline phosphatase is the main finding.³

WHAT TEST NEXT FOR OUR PATIENT?

1. What is the next most appropriate diagnostic step for our patient?

• Liver biopsy
• Ultrasonography of the liver
• Computed tomography (CT) of the liver
• Observation

Our patient has an elevated GGT level, which suggests that his elevated alkaline phosphatase is of hepatic rather than bony origin. Moreover, a serum alkaline phosphatase level that is elevated out of proportion to the aminotransferase levels reflects cholestatic liver injury.

CASE CONTINUED: ULTRASONOGRAPHY IS MOSTLY NORMAL

Ultrasonography of the right upper quadrant revealed that the liver had normal echogenicity and was mildly enlarged. There was no focal hepatic lesion. The gallbladder appeared normal, with no stones or sludge. No dilated intrahepatic or extrahepatic biliary ducts were seen. The common bile duct measured 4 mm. A small amount of ascites not amenable to paracentesis was present.

Thus, in the absence of biliary dilation on ultrasonography, we are dealing with an intrahepatic cholestatic process.

CAUSES OF CHOLESTATIC LIVER DISEASE

Viral hepatitis

Viral hepatitis most often produces a hepatocellular pattern of injury (ie, AST and ALT elevations predominate). However, in rare cases it can cause a cholestatic pattern of injury.

Our patient subsequently had serologic tests for viral hepatitis, including hepatitis A, B, and C, and the results were negative.

Autoimmune liver disease

The three most common forms of autoimmune liver disease are autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis.

Autoimmune hepatitis is characterized by high serum ALT and AST levels, whereas primary biliary cirrhosis and primary sclerosing cholangitis are associated with predominant elevations of alkaline phosphatase, since they are cholestatic disorders.

Our patient’s alkaline phosphatase level was much higher than his ALT and AST levels, making the latter two diseases more likely.

Primary biliary cirrhosis (and autoimmune hepatitis) are associated with autoantibodies in the serum, such as antinuclear antibody, smooth muscle antibody, and antimitochondrial antibody.

Our patient subsequently was tested for these antibodies, and the results were negative.

Primary sclerosing cholangitis usually affects the extrahepatic biliary system. Thus, if it is present, abnormalities should be seen on imaging.

As mentioned previously, no dilated intrahepatic or extrahepatic biliary ducts were seen on ultrasonography in our patient. Moreover, primary sclerosing cholangitis is associated with inflammatory bowel disease, particularly ulcerative colitis, which our patient did not have.

Drug-induced liver injury

Drug-induced liver injury is a common cause of cholestatic liver disease. However, our patient was not taking any prescribed, over-the-counter, or herbal medications. Additionally, he denied heavy alcohol use.

Infiltrative disorders

Infiltrative disorders such as amyloidosis, sarcoidosis, or lymphoma should be considered in the differential diagnosis of cholestatic liver disease. A clue to a possible infiltrative process is a markedly elevated level of alkaline phosphatase with a mildly increased serum bilirubin concentration, both of which our patient had.

AFTER ULTRASONOGRAPHY, WHAT IS THE NEXT STEP?

2. Which of the following is the next most appropriate diagnostic test for our patient?

• Endoscopic retrograde cholangiopancreatography (ERCP)
• Magnetic resonance cholangiopancreatography (MRCP)
• Liver biopsy
• CT of the abdomen

Figure 1 shows a proposed algorithm for evaluating increased alkaline phosphatase levels.

If there is no biliary duct dilation on ultrasonography, then abnormal levels of alkaline phosphatase most likely represent an intrahepatic pattern of cholestatic liver injury. Therefore, additional imaging with CT or magnetic resonance imaging is of limited diagnostic value. ERCP is used today for therapy rather than diagnosis, so its use is limited to patients known to have dilated biliary ducts on imaging. Liver biopsy, however, can provide useful findings.

Case continued: He undergoes biopsy

Our patient underwent transjugular liver biopsy. During the procedure, transjugular venography showed stenosis in the right, middle, and left hepatic veins and the hepatic portion of the inferior vena cava, consistent with Budd-Chiari syndrome.

The liver biopsy specimen was positive for extensive deposition of slight eosinophilic and amorphous material in a sinusoidal pattern in the liver parenchyma, as well as in the portal tracts, with markedly atrophic hepatocytes. Congo red birefringence confirmed the diagnosis of amyloidosis. The immunohistochemical phenotype was positive for kappa light chains, which is diagnostic for primary-type amyloidosis, also called amyloidosis of light chain composition, or AL.

Bone marrow aspiration and bone marrow biopsy were performed and showed 22% plasma cells, well above the normal range (0–2%), consistent with the diagnosis of multiple myeloma.

BUDD-CHIARI SYNDROME: A CHALLENGING DIAGNOSIS

Budd-Chiari syndrome is a rare condition characterized by obstruction of venous outflow from the liver at a site that may vary from the small hepatic veins up to the inferior vena cava or even the right atrium.^5,6 Obstruction of hepatic venous outflow leads to sinusoidal congestion and hypoxic damage of the hepatocytes.⁷ Hypoxia and necrosis of the hepatocytes result in the release of free radicals. Cirrhosis can eventually occur secondary to ischemic necrosis of hepatocytes and hepatic fibrosis.⁸

The estimated incidence of this syndrome is 1 in 2.5 million persons per year.⁷ It is more prevalent in women and young adults.⁸

Heterogeneous in its causes and manifestations

Budd-Chiari syndrome is also heterogeneous in its manifestations, which depend on the extent of the occlusion, on the acuteness of the obstruction, and on whether venous collateral circulation has developed to decompress the liver sinusoids.^9,12,13 Therefore, on the basis of its clinical manifestations, it can be classified as fulminant, acute, subacute, or chronic.^12–16

The fulminant form presents with hepatic encephalopathy within 8 weeks after the development of jaundice. The subacute form, which is the most common, has a more insidious onset in which hepatic sinusoids are decompressed by portal and hepatic venous collateral circulation. The patient usually presents with abdominal pain, ascites, hepatomegaly, nausea, vomiting, and mild jaundice. Finally the chronic form presents as complications of cirrhosis.^12–16

Imaging plays an important role in diagnosing Budd-Chiari syndrome

Imaging plays an important role in detecting and classifying Budd-Chiari syndrome.

Duplex ultrasonography is useful for detecting this syndrome and has a sensitivity and specificity of 85%.⁹

CT and magnetic resonance imaging can also help in the diagnosis by showing thrombosis, obstruction, or occlusion in the hepatic vein or the inferior vena cava.⁵

Venography is the gold standard for diagnosis. However, it should be performed only if noninvasive tests are negative or nondiagnostic and there is a high clinical suspicion of this disease.¹⁷ Budd-Chiari syndrome has a characteristic pattern on venography known as “spider web,” which is due to the formation of venous collaterals to bypass the occluded hepatic veins.⁹

Liver biopsy is not necessarily required to confirm the diagnosis of Budd-Chiari syndrome, but it can help in diagnosing the acute or subacute forms and also in ruling out other causes. Histologic findings can include centrizonal congestion, loss of hepatocytes, hemorrhage, and fibrosis.^18,19 Regenerative nodules are found in about 25% of patients.¹⁹

TREATING BUDD-CHIARI SYNDROME

The primary goal of treatment is to prevent further extension of the venous thrombosis in the hepatic veins, in their collaterals, and in the intrahepatic and extrahepatic portal venous system. Resolution of hepatic congestion improves liver perfusion and preserves function of the hepatocytes.

Anticoagulation is recommended in the early stages. Heparin therapy should be initiated and subsequently switched to warfarin with the goal of achieving an international normalized ratio of the prothrombin time of 2.0 to 2.5.^8,9,19

Thrombolysis is effective in the acute form.^20,21 Recanalization, including percutaneous or transhepatic angioplasty of localized segments of the narrowed hepatic veins or inferior vena cava, has long-term patency rates of 80% to 90%.²²

If thrombolytic therapy and angioplasty are unsuccessful, a transjugular intrahepatic portosystemic shunt or a surgical procedure (side-to-side portocaval shunt, central splenorenal shunt, or mesocaval shunt) should be considered.⁹

Liver transplantation is another treatment option in those with fulminant Budd-Chiari syndrome or advanced liver cirrhosis.⁸

PROGNOSIS HAS IMPROVED

The prognosis of Budd-Chiari syndrome has improved, thanks to both earlier diagnosis and new treatments. The 1-year survival rate, which was about 60% before 1985, has increased to more than 80% in recent cohort studies.¹⁹

Studies have shown that the Child-Pugh score, which is based on a combination of serum albumin, bilirubin, prothrombin time, encephalopathy, and ascites, can be considered as an independent prognostic factor. A lower Child-Pugh score and a younger age are associated with a good prognosis.^19,23,24 (The Child-Pugh score cannot be applied to our patient because he does not have cirrhosis.)

What happened to our patient?

Our patient was started on anticoagulation for his Budd-Chiari syndrome and on bortezomib (Velcade) and dexamethasone for his multiple myeloma. He achieved remarkable improvement in his liver function tests. Follow-up duplex ultrasonography 1 month after discharge revealed that the stenosis in the hepatic veins had resolved. He is following up with the oncology clinic for management of his multiple myeloma.

To the Editor: We thank Drs. Venkatachalam and Rimmerman¹ for their Clinical Picture article, “Electrocardiography in aortic regurgitation: It’s in the details,” in the August 2011 issue. This was very interesting, as usual for the Cleveland Clinic Journal of Medicine.

The maxim that “a negative U wave is never normal,” first noted about 50 years ago, still holds true. However, the authors’ statement on page 506—ie, that a negative U wave indicates structural heart disease—is too restrictive, since ischemia is not always due to a structural problem. Functional ischemia from excess demand, such as from tachycardia, sepsis, or gastrointestinal bleeding, can also cause negative U waves.^2,3 The broader comment in the “sidebar” on page 505 could be considered to include demand ischemia, but for clarity, it would be helpful to state this explicitly.

To the Editor: We thank Drs. Venkatachalam and Rimmerman¹ for their Clinical Picture article, “Electrocardiography in aortic regurgitation: It’s in the details,” in the August 2011 issue. This was very interesting, as usual for the Cleveland Clinic Journal of Medicine.

The maxim that “a negative U wave is never normal,” first noted about 50 years ago, still holds true. However, the authors’ statement on page 506—ie, that a negative U wave indicates structural heart disease—is too restrictive, since ischemia is not always due to a structural problem. Functional ischemia from excess demand, such as from tachycardia, sepsis, or gastrointestinal bleeding, can also cause negative U waves.^2,3 The broader comment in the “sidebar” on page 505 could be considered to include demand ischemia, but for clarity, it would be helpful to state this explicitly.

To the Editor: We thank Drs. Venkatachalam and Rimmerman¹ for their Clinical Picture article, “Electrocardiography in aortic regurgitation: It’s in the details,” in the August 2011 issue. This was very interesting, as usual for the Cleveland Clinic Journal of Medicine.

The maxim that “a negative U wave is never normal,” first noted about 50 years ago, still holds true. However, the authors’ statement on page 506—ie, that a negative U wave indicates structural heart disease—is too restrictive, since ischemia is not always due to a structural problem. Functional ischemia from excess demand, such as from tachycardia, sepsis, or gastrointestinal bleeding, can also cause negative U waves.^2,3 The broader comment in the “sidebar” on page 505 could be considered to include demand ischemia, but for clarity, it would be helpful to state this explicitly.

In Reply: We appreciate the comments from Drs. Suksaranjit, Cheungpasitporn, Bischof, and Marx on our recent article on the negative U wave in a patient with chronic aortic regurgitation.¹ The clinical data including electrocardiography, echocardiography, and coronary angiography were presented to emphasize the importance of identifying the negative U wave in the setting of valvular heart disease. We outlined the common differential diagnosis for a negative U wave (page 506). We believe that in the appropriate clinical setting the presence of a negative U wave provides diagnostic utility.

Several published reports to date have described the occurrence of the negative U wave in the setting of obstructive coronary artery disease^2–5 or coronary artery vasospasm.⁶ We were unable to find similar data in the setting of demand ischemia in the presence of normal coronary arteries (functional ischemia), but we fully recognize its likely occurrence, and we value the helpful insight.

In Reply: We appreciate the comments from Drs. Suksaranjit, Cheungpasitporn, Bischof, and Marx on our recent article on the negative U wave in a patient with chronic aortic regurgitation.¹ The clinical data including electrocardiography, echocardiography, and coronary angiography were presented to emphasize the importance of identifying the negative U wave in the setting of valvular heart disease. We outlined the common differential diagnosis for a negative U wave (page 506). We believe that in the appropriate clinical setting the presence of a negative U wave provides diagnostic utility.

Several published reports to date have described the occurrence of the negative U wave in the setting of obstructive coronary artery disease^2–5 or coronary artery vasospasm.⁶ We were unable to find similar data in the setting of demand ischemia in the presence of normal coronary arteries (functional ischemia), but we fully recognize its likely occurrence, and we value the helpful insight.

In Reply: We appreciate the comments from Drs. Suksaranjit, Cheungpasitporn, Bischof, and Marx on our recent article on the negative U wave in a patient with chronic aortic regurgitation.¹ The clinical data including electrocardiography, echocardiography, and coronary angiography were presented to emphasize the importance of identifying the negative U wave in the setting of valvular heart disease. We outlined the common differential diagnosis for a negative U wave (page 506). We believe that in the appropriate clinical setting the presence of a negative U wave provides diagnostic utility.

Several published reports to date have described the occurrence of the negative U wave in the setting of obstructive coronary artery disease^2–5 or coronary artery vasospasm.⁶ We were unable to find similar data in the setting of demand ischemia in the presence of normal coronary arteries (functional ischemia), but we fully recognize its likely occurrence, and we value the helpful insight.

Congestive heart failure, as noted in the review by Samala et al in this issue of the Journal, is more prevalent in the elderly. Particularly in the frail elderly, managing severe congestive heart failure poses ethical, socioeconomic, and medical challenges. The presence of even subtle cognitive impairment requires detailed dialogue with family and caregivers about medications and about symptoms that warrant a trip to the emergency room. Patients on a fixed income may not be able to afford their medications and thus may use them sporadically. And the preprepared foods they often eat are laden with sodium.

The symptoms of congestive heart failure may easily go unrecognized or be attributed to other common problems. Sorting out the reasons for exertional fatigue, especially a generalized sense of fatigue, can be particularly vexing. Anemia and sarcopenia can directly cause exertional fatigue or “weakness” but may also exacerbate heart failure and cause similar symptoms. Pharmacologic and dietary causes for volume overload must be sought. Even intermittent use of over-the-counter nonsteroidal anti-inflammatory drugs can be problematic.

Severe congestive heart failure is a lethal disease. Current quality guidelines for its treatment emphasize the use of multiple drugs and devices. Yet vasoactive drugs may not be well tolerated in frail patients, who are particularly vulnerable to orthostatic hypotension and cerebral hypoperfusion. Digoxin, of marginal benefit in younger patients without tachyarrhythmias, has an even more tenuous risk-benefit ratio in the frail elderly. Beta-blockers may cause fatigue and depression, and even low-dose diuretics can exacerbate symptoms of bladder dysfunction. Previously implanted defibrillators may be inconsistent with the patient’s current end-of-life desires.

Ideal management of the genuinely frail elderly patient with severe congestive heart failure is not always a matter of ventricular assist devices, biventricular pacers, or angiotensin-converting enzyme inhibitors. At some point, referral to palliative care resources, guided by informed input from the patient, family members, and caregivers, may be the most appropriate high-quality care that we can (and should) offer.

Congestive heart failure, as noted in the review by Samala et al in this issue of the Journal, is more prevalent in the elderly. Particularly in the frail elderly, managing severe congestive heart failure poses ethical, socioeconomic, and medical challenges. The presence of even subtle cognitive impairment requires detailed dialogue with family and caregivers about medications and about symptoms that warrant a trip to the emergency room. Patients on a fixed income may not be able to afford their medications and thus may use them sporadically. And the preprepared foods they often eat are laden with sodium.

The symptoms of congestive heart failure may easily go unrecognized or be attributed to other common problems. Sorting out the reasons for exertional fatigue, especially a generalized sense of fatigue, can be particularly vexing. Anemia and sarcopenia can directly cause exertional fatigue or “weakness” but may also exacerbate heart failure and cause similar symptoms. Pharmacologic and dietary causes for volume overload must be sought. Even intermittent use of over-the-counter nonsteroidal anti-inflammatory drugs can be problematic.

Severe congestive heart failure is a lethal disease. Current quality guidelines for its treatment emphasize the use of multiple drugs and devices. Yet vasoactive drugs may not be well tolerated in frail patients, who are particularly vulnerable to orthostatic hypotension and cerebral hypoperfusion. Digoxin, of marginal benefit in younger patients without tachyarrhythmias, has an even more tenuous risk-benefit ratio in the frail elderly. Beta-blockers may cause fatigue and depression, and even low-dose diuretics can exacerbate symptoms of bladder dysfunction. Previously implanted defibrillators may be inconsistent with the patient’s current end-of-life desires.

Ideal management of the genuinely frail elderly patient with severe congestive heart failure is not always a matter of ventricular assist devices, biventricular pacers, or angiotensin-converting enzyme inhibitors. At some point, referral to palliative care resources, guided by informed input from the patient, family members, and caregivers, may be the most appropriate high-quality care that we can (and should) offer.

Congestive heart failure, as noted in the review by Samala et al in this issue of the Journal, is more prevalent in the elderly. Particularly in the frail elderly, managing severe congestive heart failure poses ethical, socioeconomic, and medical challenges. The presence of even subtle cognitive impairment requires detailed dialogue with family and caregivers about medications and about symptoms that warrant a trip to the emergency room. Patients on a fixed income may not be able to afford their medications and thus may use them sporadically. And the preprepared foods they often eat are laden with sodium.

The symptoms of congestive heart failure may easily go unrecognized or be attributed to other common problems. Sorting out the reasons for exertional fatigue, especially a generalized sense of fatigue, can be particularly vexing. Anemia and sarcopenia can directly cause exertional fatigue or “weakness” but may also exacerbate heart failure and cause similar symptoms. Pharmacologic and dietary causes for volume overload must be sought. Even intermittent use of over-the-counter nonsteroidal anti-inflammatory drugs can be problematic.

Severe congestive heart failure is a lethal disease. Current quality guidelines for its treatment emphasize the use of multiple drugs and devices. Yet vasoactive drugs may not be well tolerated in frail patients, who are particularly vulnerable to orthostatic hypotension and cerebral hypoperfusion. Digoxin, of marginal benefit in younger patients without tachyarrhythmias, has an even more tenuous risk-benefit ratio in the frail elderly. Beta-blockers may cause fatigue and depression, and even low-dose diuretics can exacerbate symptoms of bladder dysfunction. Previously implanted defibrillators may be inconsistent with the patient’s current end-of-life desires.

Ideal management of the genuinely frail elderly patient with severe congestive heart failure is not always a matter of ventricular assist devices, biventricular pacers, or angiotensin-converting enzyme inhibitors. At some point, referral to palliative care resources, guided by informed input from the patient, family members, and caregivers, may be the most appropriate high-quality care that we can (and should) offer.

Mr. R. is an 85-year-old with congestive heart failure; the last time his ejection fraction was measured it was 30%. He also has hypertension, coronary artery disease (for which he underwent triple-vessel coronary artery bypass grafting), osteoarthritis, hyperlipidemia, and chronic obstructive pulmonary disease. He currently takes lisinopril (Zestril), carvedilol (Coreg), aspirin, clopidogrel (Plavix), digoxin, simvastatin (Zocor), furosemide (Lasix), an albuterol inhaler (Proventil), and over-the-counter naproxen (Naprosyn), the last two taken as needed.

Accompanied by his daughter, Mr. R. comes to see his primary care physician for a routine follow-up visit. He says he feels fine and has no shortness of breath or chest pain, but he feels light-headed at times, especially when he gets out of bed. He also mentions that he is bothered with having to get up three to four times at night to urinate.

On further questioning, he relates that he uses a cane to walk around the house and gets short of breath when walking from his bed to the bathroom and from one room to the next. He can feed himself, but he needs assistance with bathing and getting dressed.

Mr. R. admits that he has been feeling lonely since his wife died about a year ago. He now lives with his daughter and her family, and they all get along well. His daughter mentions that over the last 6 months he has not been eating well, that he appears to have lost interest in doing some of the things that he used to enjoy, and that he has lost weight. She adds that he has fallen twice in the last month.

On physical examination, Mr. R. is without distress but appears weak. He answers all questions appropriately, although his affect is flat and his daughter fills in some of the details.

Supine, his blood pressure is 160/90 mm Hg and his heart rate is 75; immediately after standing up he feels dizzy and his blood pressure drops to 120/60 mm Hg with a heart rate of 110. Three months ago he weighed 155 pounds (70.3 kg); today he weighs 145 pounds (65.9 kg).

His neck veins are not distended. On chest auscultation, bibasilar coarse crackles are heard, as well as a systolic murmur (grade 2 on a scale of 6), loudest in the second intercostal space at the right parasternal border. No peripheral edema is detected. His Mini-Mental State Exam score is 22 out of 30.

What changes, if any, should be made in Mr. R.’s management? What advice should the primary care physician give Mr. R. and his daughter about the course of his heart failure?

THE IMPORTANCE OF COMPLETE CARE

Mr. R. has multiple convoluted medical issues that plague many elderly patients with heart failure. To provide optimal care to patients like him, physicians need to draw on knowledge from the fields of internal medicine, geriatrics, and cardiology.

In this paper, we discuss how diagnosing and managing heart failure is different in elderly patients. We emphasize the importance of complete care of frail elderly patients, highlighting the pharmacologic and nonpharmacologic interventions that are available. Finally, we will return to Mr. R. and discuss a comprehensive plan for him.

HEART FAILURE, FRAILTY, DISABILITY ARE ALL CONNECTED

The ability to bounce back from physical insults, chiefly medical illnesses, sharply declines in old age. As various stressors accumulate, physical deterioration becomes inevitable. While some older adults can avoid going down this path of morbidity, in an increasing number of frail elderly patients, congestive heart failure inescapably assumes a complicated course.

Frailty is a state of increased vulnerability to stressors due to age-related declines in physiologic reserve.¹ Two elements intimately related to frailty are comorbidity and disability.

Fried et al² analyzed data from more than 5,000 older men and women in the Cardiovascular Health Study and concluded that comorbidity (ie, having two or more chronic diseases) is a risk factor for frailty, which in turn results in disability, falls, hospitalizations, and death.

The relationship between congestive heart failure and frailty is complex. Not only does heart failure itself result in frailty, but its multiple therapies can put additional stress on a frail patient. In addition, the heart failure and its treatments can negatively affect coexisting disorders (Figure 1).

BY THE NUMBERS

Heart failure is largely a disorder of the elderly, and as the US population ages, heart failure is rising in prevalence to epidemic numbers.³ The median age of patients admitted to the hospital because of heart failure is 75,⁴ and patients age 65 and older account for more than 75% of heart failure hospitalizations.⁵ Every year, in every 1,000 people over age 65, nearly 10 new cases of heart failure are diagnosed.⁶

Before age 70, men are affected more than women, but the opposite is true at age 70 and beyond. The reason for this reversal is that women live longer and have a better prognosis, as the cause of heart failure in most women is diastolic dysfunction secondary to hypertension rather than systolic dysfunction due to coronary artery disease, as in most men.⁷

Heart failure is costly and generally has a poor prognosis. The total cost of treating it reached a staggering $37.2 billion in 2009, and it was the leading cause of Medicare hospital admissions.⁶ Heart failure is the primary cause or a contributory cause of death in about 290,000 patients each year, and the rate of death at 1 year is an astonishing 1 in 5.⁶ The median survival time after diagnosis is 2.3 to 3.6 years in patients ages 67 to 74, and it is considerably shorter—1.1 to 1.6 years—in patients age 85 and older.⁸

THE BROKEN HEART

In 2005, the American College of Cardiology and the American Heart Association defined congestive heart failure as “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.”⁹ This characterization captures the intricate nature of the disease: its spectrum of symptoms, its many causes (eg, coronary artery disease, hypertension, nonischemic or idiopathic cardiomyopathy, and valvular heart disease), and the dual pathophysiologic features of systolic and diastolic impairment.

Systolic vs diastolic failure

Of the various ways of classifying heart failure, the most important is systolic vs diastolic.

The hallmark of systolic heart failure is a decreased left ventricular ejection fraction, and it is characterized by a large thin-walled ventricle that is weak and unable to eject enough blood to generate a normal cardiac output.

In contrast, the ejection fraction is normal or nearly normal in diastolic heart failure, but the end-diastolic volume is decreased because the ventricle is hypertrophied and thick-walled. The resultant chamber has become small and stiff and does not have enough volume for sufficient cardiac output.

QUIRKS IN THE HISTORY AND PHYSICAL EXAMINATION

The combination of inactivity and coexisting illnesses in a frail older adult may obscure some of the usual clinical manifestations of heart failure. While shortness of breath on mild exertion, easy fatigability, and leg swelling are common in younger heart failure patients, these symptoms may be due to normal aging in a much older patient. Let us consider some important aspects of the common signs and symptoms associated with heart failure.

Dyspnea on exertion is one of the earliest and most prominent symptoms. The usual question asked of patients to elicit whether this key manifestation is present is, “Do you get short of breath after walking a block?” However, this question may not be appropriate for a frail elderly person whose activity is restricted by comorbidities such as severe arthritis, coronary artery disease, or peripheral arterial disease. For a patient like this, ask instead if he or she gets short of breath after milder forms of exertion, such as making the bed, walking to the bathroom, or changing clothes.¹⁰ Also, keep in mind that dyspnea on exertion may be due to other conditions, such as renal failure, lung disease, depression, anemia, or deconditioning.

Orthopnea and paroxysmal nocturnal dyspnea may not be volunteered or elicited if a patient is sleeping in a chair or a recliner.

Leg swelling is less specific in older adults than in younger patients because chronic venous insufficiency is common in older people.

Weight gain almost always accompanies symptomatic heart failure but may also be due to increased appetite secondary to depression.

A change in mental status is common in elderly people with heart failure, especially those with vascular dementia with extensive cerebrovascular atherosclerosis or those who have latent Alzheimer disease.¹⁰

Cough, a symptom of a multitude of disorders, may be an early or the only manifestation of heart failure.

Pulmonary crackles are typically detected in most heart failure patients, but they may not be as characteristic in older adults, as they may also be noted in bronchitis, pneumonia, and other chronic lung diseases.

Additional symptoms to watch for include fatigue, syncope, angina, nocturia, and oliguria.

The bottom line is to integrate individual findings with other elements of the history and physical examination in diagnosing heart failure and tracking its progression.

CLINCHING THE DIAGNOSIS

Congestive heart failure is essentially a clinical diagnosis best established even before ordering tests, especially during times and situations in which these tests are not always readily available, such as outside office hours and in a long-term care setting.

A reliable and thorough history and physical examination is the most important component of the diagnostic process.

An echocardiogram is obtained next to measure the ejection fraction, which has both prognostic and therapeutic significance. Echocardiography can also uncover potential contributory cardiac structural abnormalities.

A chest radiograph is also typically obtained to look for pulmonary congestion, but in older adults its interpretation may be skewed by chronic lung disease or spinal deformities such as scoliosis and kyphosis.

The B-type natriuretic peptide (BNP) level is a popular blood test. BNP is commonly elevated in patients with heart failure. However, an elevated level in older adults should always be evaluated within the context of other clinical findings, as it can also result from advancing age and diseases other than heart failure, such as coronary artery disease, chronic pulmonary disease, pulmonary embolism, and renal insufficiency.^11,12

PHARMACOTHERAPY PEARLS

Drug treatment for heart failure has evolved rapidly. Robust and sophisticated clinical trials have led to guidelines that call for specific medications. Unfortunately, older patients, particularly the very old and frail, have been poorly represented in these studies.⁹ Nonetheless, the type and choice of drugs for the young and old are similar.

Take into account age-associated changes in pharmacokinetics

Age-associated changes in pharmacokinetics must be taken into account when prescribing drugs for heart failure.¹³

Oral absorption of cardiovascular drugs is not significantly affected by the various changes that occur in older adults (eg, reduced gastric acid production, gastric emptying rate, gastrointestinal blood flow, and mobility). However, reductions in both lean body mass and total body water that come with aging result in lower volumes of distribution and higher plasma concentrations of hydrophilic drugs, most notably angiotensin-converting enzyme (ACE) inhibitors and digoxin. In contrast, the plasma concentrations of lipophilic drugs such as beta-blockers and central alpha-agonists tend to decrease as the proportion of body fat increases in older adults.

As the plasma albumin level diminishes with age, the free-drug concentration of salicylates and warfarin (Coumadin), which are extensively albumin-bound, may increase.

The serum concentrations of cardiovascular drugs metabolized in the liver—eg, propranolol (Inderal), lidocaine, labetalol (Trandate), verapamil (Calan), diltiazem (Cardizem), nitrates, and warfarin—may be elevated due to reduced hepatic blood flow, mass, volume, and overall metabolic capacity.

Declines in renal blood flow, glomerular filtration, and tubular function may cause accumulation of drugs that are excreted through the kidneys.

Beware of toxicities

Table 1 lists some of the drugs used in treating heart failure, common adverse affects to watch for, and recommendations for their use.

WIELDING THE SCALPEL

A tenet of heart failure management is to correct the underlying cardiac structural abnormality. This often calls for invasive intervention along with optimization of drug therapy.

For example:

• Diseased coronary arteries may be amenable to revascularization, either by percutaneous coronary intervention or by the much more involved coronary artery bypass grafting, with the aim of enhancing cardiac function.
• Valves can be repaired or replaced in patients with valvular heart disease.
• A pacemaker can be implanted to remedy sick sinus syndrome, especially with concurrent use of heart-rate-lowering agents such as beta-blockers.
• Placement of an implantable cardioverter-defibrillator has been found to be effective in preventing death due to ventricular tachyarrhythmias in patients with an ejection fraction of less than 30%.⁹
• Cardiac resynchronization with a biventricular pacemaker may increase the ejection fraction and cardiac output by eliminating dyssynchronous contraction of the left and right ventricles.¹⁴

In frail older adults, consideration of these invasive therapies must be individualized. While procedures such as percutaneous coronary intervention and pacemaker placement may not be as physically taxing as bypass grafting or valve replacement, the potential for surgical complications must be seriously considered, particularly if the patient has diminished physiologic reserve. Case-to-case consideration is also crucial in cardioverter-defibrillator insertion, as the survival benefit may be diminished in older adults, who likely have coexisting illnesses that predispose them to die of a noncardiac cause.^15,16

The bottom line is to contemplate multiple factors—severity of the heart failure, comorbidities, baseline functional status, and social support—when assessing the appropriateness of an invasive intervention.

BEYOND DRUGS AND DEVICES: WE CAN DO ‘MORE’

Much of the spotlight has been on the various drugs and devices used to treat heart failure, but of equal importance for frail elderly patients are complementary approaches that can be used to ease disease progression and boost the quality of life. The acronym MORE highlights these strategies.

M: Multidisciplinary management programs

Heart failure disease-management programs are designed to provide comprehensive multidisciplinary care across different settings (ie, home, outpatient, and inpatient) to high-risk patients who often have multiple medical, social, and behavioral issues.⁹ Interventions usually include intensive patient education, encouraging patients to be more aggressive participants in their care, closely monitoring patients through telephone follow-up or home nursing, carefully reviewing medications to improve adherence to evidence-based guidelines, and multidisciplinary care with nurse case management directed by a physician.

Studies have shown that management programs, which were largely nurse-directed and targeted at older adults and patients with advanced disease, can improve quality of life and functional status, decrease hospitalizations for both heart failure and other causes, and decrease medical costs.^17–19

O: Other diseases

R: Restrictions

Specific limitations in the intake of certain dietary elements are a valuable adjunct in heart failure management.

Sodium intake should be restricted to less than 3 g/day by not adding salt to meals and by avoiding salt-rich foods (eg, canned and processed foods).²⁴ During times of distressing volume overload, a tighter sodium limit of 2 g/day is necessary, and diuretics may be less effective if this restriction is not implemented.

Fluid restriction depends on the patient’s clinical status.²⁵ While it is not necessary to limit fluid intake in the absence of retention, a limit of 2 L/day is recommended if edema is detected. If volume overload is severe, the limit should be 1 L/day.

Alcohol is a myocardial depressant that reduces the left ventricular ejection fraction.²⁶ Abstinence is a must for patients with alcohol-induced heart failure; otherwise, a limit of 1 drink (8 oz of beer, 4 oz of wine, or 1 oz of hard liquor) per day is suggested.²⁴

Calories and fat intake are both important to watch, particularly in patients with obesity, hyperlipidemia, hypertension, or coronary artery disease.

 

 

E: End-of-life issues

Usual causes of death in patients with heart failure include sudden cardiac death, arrhythmias, hypotension, end-organ hypoperfusion, and metabolic derangement.^27,28

Given the life-limiting nature of the disease in frail older adults, it is very important for clinicians to discuss end-of-life matters with patients and their families as early as possible. Needed are effective communication skills that foster respect, empathy, and mutual understanding.

Advance directives. The primary task is to encourage patients to develop advance health directives. These are legal documents that represent patients’ preferences about interventions available toward the end of life such as do-not-resuscitate orders, appointment of surrogate decision-makers, and use of life-sustaining interventions (eg, a feeding tube, dialysis, blood transfusions). Establishing these directives early on will help ease the transition from one mode of care to another (eg, from acute care to hospice care), prevent pointless use of resources (eg, emergency room visits, hospital admissions), and ensure that the patient’s wishes are carried out.

Palliative measures that aim to alleviate suffering and promote quality of life and dignity are available for patients with severe symptoms. For varying degrees of dyspnea, diuretics, nitrates, morphine, and positive inotropic agents such as dobutamine (Dobutrex) and milrinone (Primacor) can be tried. Thoracentesis is done in patients with extensive pleural effusion. Fatigue and anorexia are due to a combination of factors, namely, decreased cardiac output, increased neurohormone levels, deconditioning, depression, decreased sleep, and anxiety.²⁹ Opioids, caffeine, exercise, oxygen, fluid and salt restriction, and correction of anemia and depression may help ease these symptoms.

For patients with an implantable cardioverter-defibrillator, deactivation is an important matter that needs to be addressed. Deactivation can be carried out with certainty once the goal of care has shifted away from curative efforts and either the patient or a surrogate decision-maker has made the informed decision to turn the device off. Berger³⁰ raised three points that the clinician and decision-maker can discuss in trying to achieve a resolution during times of doubt and indecision:

• The patient may no longer value continued survival
• The device may no longer offer the prospect of increased survival
• The device may impede active dying.

The idea of hospice care should be gradually and gently explored to ensure a prompt and seamless transition when the time comes. The patient and family need to know that the goal of hospice care is to ensure comfort and that they can benefit the most by enrolling early during the course of the terminal illness.

The Medicare hospice benefit is granted to patients who have been certified by two physicians to have a life expectancy of 6 months or less if their terminal illness runs its natural course. The criteria for determining that heart failure is terminal are:

• New York Heart Association class III (symptomatic with less than ordinary activities) or IV (symptomatic at rest)
• Left ventricular ejection fraction less than or equal to 20%
• Persistent symptoms despite optimal medical management
• Inability to tolerate optional management due to hypotension with or without renal failure.³¹

WHAT CAN WE DO FOR MR. R.?

Mr. R. has systolic heart failure stemming from coronary artery disease, and his symptoms put him in New York Heart Association class III. He is well managed with drugs of different appropriate classes: an ACE inhibitor, a beta-blocker, digoxin, an aldosterone antagonist, and a diuretic. His other drugs all have well-defined indications.

Since he does not have fluid overload, his furosemide can be stopped, and this change will likely relieve his orthostatic hypotension and nocturia. His systolic blood pressure target can be liberalized to 150 mm Hg or less, as tighter control might exacerbate orthostatic hypotension. This change, along with having him start using a walker instead of a cane, will hopefully prevent future falls. Furthermore, his naproxen should be discontinued, as it can worsen heart failure.

Mr. R. has symptoms of depression and thus needs to be started on an antidepressant and encouraged to engage in social activities as much as he can tolerate. These interventions may also help with his mild dementia, which is evidenced by a Mini-Mental State Exam score of 22. He will not benefit from sodium and fat restriction, as he has actually been losing weight.

To keep Mr. R.’s cognitive impairment and overall decline in function from compromising his compliance with his treatment, he will need a substantial amount of assistance, which his daughter alone may not be able to provide. To tackle this concern, a discussion about participating in a heart failure management program can be started with Mr. R. and his family.

More importantly, his advanced directives, including delegating a surrogate decision-maker and deciding on do-not-resuscitate status, have to be clarified. Finally, it would be prudent to introduce the concept of hospice care to the patient and his daughter while he is still coherent and able to state his preferences.